🧬 Part ONE — BASIC CONCEPTS v3

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1 Chapter 1

1 CHROMOSOMAL MORPHOLOGY
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Elements of Medical Cytogenetics 5 CHROMOSOMAL MORPHOLOGY Chromosomes have a linear appearance: two arms that are continuous at the centromere.医学细胞遗传学要素 5 染色体形态学 染色体呈线性外观：两条臂在着丝粒处连续。
Reflecting the French influence in the establishment of the cytogenetic nomenclature, the shorter arm is designated p (for petit), and the longer is q.2 In the early part of the cell cycle, each chromosome is present as a single structure, a chromatid, a single (but 2-stranded) DNA molecule.反映法国在建立细胞遗传学命名法方面的影响，较短的臂被命名为p（源自petit），较长的臂为q。2 在细胞周期早期，每条染色体以单一结构存在，即一条染色单体，是一个单链（但双股）DNA分子。
During the cell cycle, the chromosomes replicate, and two sister chromatids form.在细胞周期中，染色体复制，形成两条姐妹染色单体。
Now the chromosome exists as a double-chromatid entity.此时染色体以双染色单体实体存在。
Each chromatid contains exactly the same genetic material.每条染色单体含有完全相同的遗传物质。
This replication is in preparation for cell division so that, after the chromosome has separated into its two component chromatids, each daughter cell receives the full amount of genetic material.这种复制是为细胞分裂做准备，以便染色体分离成两条组成染色单体后，每个子细胞获得完整的遗传物质。
It is during mitosis that the chromosomes contract and become readily distinguishable on light microscopy.正是在有丝分裂期间，染色体收缩并在光学显微镜下易于区分。
Blood and buccal mucosal cells are the tissues from which DNA is extracted in routine chromosome analysis.血液和颊黏膜细胞是常规染色体分析中提取DNA的组织。
From blood, the nucleated white cell is the tested component for microarray analysis, and in classical cytogenetic analysis, it is the lymphocyte.来自血液的有核白细胞是微阵列分析中的检测成分，而在经典细胞遗传学分析中，则是淋巴细胞。
Buccal mucosal cells and white blood cells are obtained from a saliva sample.颊黏膜细胞和白细胞来自唾液样本。
The chromosomal status of each small sample is taken as representative of the constitution of (essentially) every other cell of the body.每个小样本的染色体状态被视为代表身体（基本上）所有其他细胞的组成。
In the case of invasive prenatal diagnosis, the cells from amniotic fluid or chorionic villi are the source material; these tissues are assumed (with certain caveats) to represent the fetal chromosomal constitution.在侵入性产前诊断中，羊水或绒毛膜绒毛的细胞是源材料；这些组织（在特定条件下）被认为代表胎儿染色体组成。
Noninvasive prenatal testing exploits the presence of fetal blood cells and DNA in the maternal circulation.无创产前检测利用母体循环中存在的胎儿血细胞和DNA。
Preimplantation diagnosis analyzes a few cells taken from the trophoblast of an embryo at in vitro fertilization (IVF).植入前诊断分析取自体外受精胚胎滋养层的少数细胞。
The 46 chromosomes come in 23 matching pairs and constitute the genome.46条染色体组成23对匹配对，构成基因组。
One of each pair came from the mother, and one from the father.每对染色体中一条来自母亲，一条来自父亲。
For 22 of the chromosome pairs, each member (each homolog) has the same morphology in each sex: These are the autosomes.对于22对染色体，每个成员（每个同源染色体）在两性中具有相同形态：这些是常染色体。
The sex chromosome (or gonosome) constitution differs: The female has a pair of X chromosomes, and the male has an X and a Y chromosome.性染色体组成不同：女性有一对X染色体，男性有一条X和一条Y染色体。
The single set of 23 homologs—one of each autosome plus one sex chromosome—is the haploid set, and thus the haploid number (n) is 23.单套23条同源染色体——每条常染色体一条加上一条性染色体——是单倍体组，因此单倍体数（n）为23。
The haploid complement exists, as such, only in the gametocytes (ovum and sperm).单倍体补体仅存在于配子细胞（卵子和精子）中。
All other cells in the body—the soma—have a double set: the diploid complement (2n) of 46.身体中的所有其他细胞——体细胞——都有一套双份的染色体：46条染色体的二倍体（2n）。
If there is a difference between a pair of homologs, in the sense of one being structurally rearranged, the person is described as a heterozygote.如果一对同源染色体之间存在差异，即其中一条发生了结构重排，则该个体被称为杂合子。
The chromosomes are classically distinguishable on the basis of their size, centromere position, and banding pattern.染色体传统上可根据其大小、着丝粒位置和带型进行区分。
The centromere may be in the middle, off-center, or close to one end—metacentric, submetacentric, and acrocentric, respectively.着丝粒可能位于中间、偏离中心或靠近一端——分别称为中着丝粒、亚中着丝粒和近端着丝粒。
The chromosomes are numbered 1 through 22, and X and Y, and are also assigned to groups A through G, according to their general size and the position of the centromere.染色体按1到22号编号，以及X和Y染色体，并根据其大致大小和着丝粒位置被分配到A到G组。
The diagrammatic representation of the banding pattern is the ideogram (Appendix A).带型的图解表示称为染色体模式图（附录A）。
The numbering is based on size, largest to smallest (to split hairs, this order is not exact; for 2 Variously explained as being the next letter in the alphabet, a mistyping of g (for grand), for queue, or as the other letter in the formula p + q = 1.编号基于大小，从最大到最小（严格来说，这个顺序并不精确；例如，10号和11号染色体比12号染色体短，而21号染色体比22号小）。
2 CHROMOSOMAL STRUCTURE
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6 BASIC CONCEPTS example, chromosomes 10 and 11 are shorter than chromosome 12, and chromosome 21 is smaller than 22).6 基本概念 例如，10号和11号染色体比12号染色体短，而21号染色体比22号小。
The classical format of a chromosome display, the karyotype, has the chromosomes lined up with p arms upward, in their matching pairs (Figure 1–3).染色体展示的经典格式——核型——将染色体按匹配对排列，p臂朝上（图1-3）。
Those coming from a DNA-based view may see the chromosome lying on its side, and microarray reports usually show a horizontal depiction of the chromosome arms, with the graph indicating duplications and deletions by a rise or a fall compared to baseline, respectively (although no one is proposing that short and long arms be renamed as left and right!).从DNA角度出发的人可能将染色体视为侧卧状态，而微阵列报告通常以水平方式描绘染色体臂，图表通过相对于基线的上升或下降分别表示重复或缺失（尽管没有人提议将短臂和长臂改名为左臂和右臂！）。
Karyotypes are described according to a shorthand notation, the International System of Human Cytogenetic Nomenclature (ISCN 2024); an outline is given in Appendix B.核型根据一种简写符号——国际人类细胞遗传学命名系统（ISCN 2024）进行描述；附录B中给出了概要。
In this age of “molecular karyotyping,” chromosomes are more readily being thought of as lengths of DNA, rather than as segments of stainable chromatin.在这个“分子核型分析”的时代，染色体更容易被视为DNA的长度，而非可染色的染色质片段。
A laboratory report may be couched in terms of the actual DNA content of an imbalance (Chapter 2).实验室报告可能以不平衡的实际DNA含量来表述（第2章）。
It is almost as though we can “see” the genes, rather than just knowing intellectually that this is—of course—what a chromosome consists of.几乎就像我们能够“看到”基因，而不仅仅是在理智上知道这当然是染色体的组成成分。
Table 1–1 and Figure 1–4 set out the amounts of DNA and the number of genes carried by each chromosome.表1-1和图1-4列出了每条染色体所携带的DNA量和基因数量。
CHROMOSOMAL STRUCTURE Chromatin exists in differently condensed forms: the less condensed euchromatin and the more condensed heterochromatin.染色体结构 染色质以不同凝聚形式存在：较少凝聚的常染色质和更多凝聚的异染色质。
Euchromatin contains the coding DNA—the genes—while heterochromatin comprises non-coding DNA.常染色质包含编码DNA——即基因——而异染色质由非编码DNA组成。
Chromosomes are capped Figure 1–3.染色体末端被加帽 图1-3。
Chromosomes arranged as a formal karyotype, from a classical cytogenetic study based upon a mitotic cell.染色体以正式核型排列，来自基于有丝分裂细胞的经典细胞遗传学研究。
Elements of Medical Cytogenetics 7 at the terminal extremities of their long and short arms by telomeres, specialized DNA sequences comprising many repeats of the sequence TTAGGG, that can be thought of as “sealing” the chromatin and preventing its fusion with the chromatin of other chromosomes.医学细胞遗传学要素 7 在其长臂和短臂的末端由端粒覆盖，端粒是包含多个TTAGGG重复序列的特化DNA序列，可被视为“密封”染色质，防止其与其他染色体的染色质融合。
The centromere3 is a specialized region of DNA that, at cell division, provides the Table 1–1.着丝粒3是DNA的一个特化区域，在细胞分裂时提供表1–1。
The Lengths of the Chromosomes in Megabases, the Number of Genes per Chromosome, and the Density of Genes per Chromosome CHROMOSOME LENGTH IN Mb GENES GENES PER Mb 1 249.3 1959 7.86 2 243.2 1184 4.87 3 198.0 1029 5.20 4 191.2 721 3.77 5 180.9 835 4.62 6 171.1 1002 5.86 7 159.1 855 5.37 8 146.4 638 4.36 9 141.2 748 5.30 10 135.5 714 5.27 11 135.0 1236 9.16 12 133.9 987 7.37 13 115.2 305 2.65 14 107.3 577 5.37 15 102.5 547 5.33 16 90.4 783 8.67 17 81.2 1111 13.68 18 78.1 257 3.29 19 59.1 1332 22.53 20 63.0 518 8.22 21 48.1 213 4.43 22 51.3 418 8.15 X 155.3 806 5.19 Y 59.4 65 1.09 Notes: The relative sparsity of genes on the three classic “trisomic” chromosomes, 13, 18, and 21 (and as also evident in Figure 1–4) is to be noted.以兆碱基为单位的染色体长度、每条染色体的基因数以及每条染色体的基因密度 染色体 长度（Mb） 基因数 每Mb基因数 1 249.3 1959 7.86 2 243.2 1184 4.87 3 198.0 1029 5.20 4 191.2 721 3.77 5 180.9 835 4.62 6 171.1 1002 5.86 7 159.1 855 5.37 8 146.4 638 4.36 9 141.2 748 5.30 10 135.5 714 5.27 11 135.0 1236 9.16 12 133.9 987 7.37 13 115.2 305 2.65 14 107.3 577 5.37 15 102.5 547 5.33 16 90.4 783 8.67 17 81.2 1111 13.68 18 78.1 257 3.29 19 59.1 1332 22.53 20 63.0 518 8.22 21 48.1 213 4.43 22 51.3 418 8.15 X 155.3 806 5.19 Y 59.4 65 1.09 注：需注意三个经典“三体”染色体13、18和21上基因的相对稀疏（如图1–4所示）。
In contrast, chromosome 19, although one of the smallest, carries an extraordinary load of genes.相比之下，染色体19虽然是最小的染色体之一，却携带了异常多的基因。
This, presumably, is the basis of the extreme lethality of trisomy 19 (see Figure 20– 22).这大概就是三体19极端致死性的基础（见图20–22）。
The lengths here (from hg19,a of the time) differ slightly from those listed in Table A–1, based upon hg38. a“hg”—human genome—refers to the UCSC (University of California Santa Cruz) Genome Browser assembly number.这里的长度（来自当时的hg19a）与基于hg38的表A–1中列出的长度略有不同。a“hg”——人类基因组——指UCSC（加州大学圣克鲁兹分校）基因组浏览器组装编号。
The similar GRCh (Genome Reference Consortium, human) database now uses the same numbering system, both currently 38; previously they had had different numbers, and hg37 matched CGRh19.类似的GRCh（基因组参考联盟，人类）数据库现在使用相同的编号系统，目前均为38；此前它们有不同的编号，hg37与CGRh19匹配。
These two databases are “reference genomes” that are periodically updated.这两个数据库是定期更新的“参考基因组”。
Source: After S Scherer, Guide to the Human Genome, Cold Spring Harbor Laboratory Press, Woodbury, New York, 2010. 3 When considering the physical structure of rearranged chromosomes, it is useful to keep in mind the absolute requirement for a centromere to be present on every chromosome.来源：摘自S Scherer，《人类基因组指南》，冷泉港实验室出版社，纽约州伍德伯里，2010年。3 在考虑重排染色体的物理结构时，牢记每条染色体绝对需要存在一个着丝粒是有用的。
There is also the need for each chromosome to have two telomeres, the single exception being when the rearranged chromosome forms a ring.每条染色体还需要有两个端粒，唯一的例外是当重排染色体形成一个环时。
3 CHROMOSOME ABNORMALITY
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8 BASIC CONCEPTS site at which the spindle apparatus can be anchored and draw each separated chromatid4 to opposite poles of the dividing cell.8 基本概念 纺锤体装置可以锚定并将每个分离的染色单体4拉向分裂细胞相对两极的位点。
Centromeric heterochromatin contains “satellite DNA,” so called because these DNA species have different buoyant densities and produce distinct humps on a density gradient distribution. (These are not to be confused with the satellites on acrocentric chromosomes.) A separate issue, of considerable academic interest (but which we shall take no further here), is the “packaging question”: how the centimeters of DNA are compacted into micron-length chromosomes, and which parts of the nucleus each chromosome occupies (Figure 1–5) (Sehgal et al. 2016; Sedat et al. 2022; Labade et al. 2024).着丝粒异染色质含有“卫星DNA”，之所以这样称呼是因为这些DNA种类具有不同的浮力密度，并在密度梯度分布上产生明显的峰。（这些不应与近端着丝粒染色体上的随体混淆。）另一个具有相当学术意义（但我们在此不再进一步讨论）的问题是“包装问题”：厘米级的DNA如何被压缩成微米级的染色体，以及每条染色体占据细胞核的哪些部分（图1–5）（Sehgal等人，2016；Sedat等人，2022；Labade等人，2024）。
Neither do we delve into the molecular anatomy of the chromosome, while it did not escape our notice5 that the DNA sequences within, now so well documented (Nurk et al. 2022), are, of course, their sine qua non.我们也不深入探讨染色体的分子解剖学，尽管我们没有忽略5这样一个事实：其中现已充分记录的DNA序列（Nurk等人，2022）当然是其必要条件。
CHROMOSOME ABNORMALITY Chromosomes are distributed to each daughter cell during cell division in a very precise process—precise, but prone to error.染色体异常 染色体在细胞分裂过程中以非常精确的过程分配到每个子细胞——精确，但容易出错。
From our perspective, the two cell divisions of meiosis, during which the gametes are formed, are of central importance.从我们的角度来看，减数分裂的两次细胞分裂（在此期间配子形成）至关重要。
Much of the discipline of medical cytogenetics focuses on the consequences of disordered meiosis having produced a chromosomally abnormal gamete, causing a chromosomal abnormality in the conceptus.医学细胞遗传学的许多学科都关注减数分裂紊乱产生染色体异常配子，从而导致受精卵染色体异常的后果。
A chromosome abnormality that is present from conception and involves the entire body is a constitutional abnormality.从受孕时就存在并涉及整个身体的染色体异常是体质性异常。
If an additional cell line with a different chromosomal complement arises before the basis of the body structure is formed (that is, in embryonic or pre-embryonic life) and becomes an integral part of the organism, constitutional mosaicism results.如果在身体结构形成之前（即在胚胎或前胚胎生命期）出现一个具有不同染色体组成的额外细胞系，并成为生物体的组成部分，则会导致体质性嵌合体。
In this book, we concern ourselves practically solely with constitutional abnormalities.在本书中，我们实际上只关注体质性异常。
Acquired chromosomal abnormality of course exists, and indeed it is a major initiating and sustaining cause in most cancers, a fact first proposed by Boveri in 1914 and voluminously attested in the work Figure 1–4.获得性染色体异常当然存在，并且它确实是大多数癌症的主要起始和维持原因，这一事实最早由Boveri在1914年提出，并在图1–4的工作中得到大量证实。
A Display of the DNA Content, and the Gene Load, of Each Chromosome.每条染色体的DNA含量和基因负荷的展示。
Notes: Chromosomes are ordered by size (left) and gene content (right).染色体按大小（左）和基因含量（右）排序。
The “viable” autosomes, 13, 18, and 21, are shown in blue, and the sex chromosomes in red and green.“可存活”的常染色体（13、18和21号）以蓝色显示，性染色体以红色和绿色显示。
The low gene content of the viable autosomes is evident; the bar (right) is set at 327 genes.常染色体中低基因含量是显而易见的；右侧的柱状图设定在327个基因。
Source: From EM Torres, Consequences of gaining an extra chromosome, Chromosome Res 31:24, 2023.从EM Torres的《获得额外染色体的后果》，染色体研究31:24，2023年。
Courtesy EM Torres, and with the permission of Springer Nature. 4 Chromatids separate at mitosis and at meiosis II, and at “predivision” in meiosis I. 5 A nod to Watson and Crick.承蒙EM·托雷斯惠允，并获施普林格·自然许可。 4 染色单体在 mitosis 和 meiosis II 中分离，并在 meiosis I 的“预分裂”中分离。 5 向沃森和克里克致敬。
Elements of Medical Cytogenetics 9 of Mitelman et al. (2024); but this is more the field of study of the molecular pathologist than the genetic counselor.医学细胞遗传学要素 Mitelman等人（2024）的第9部分；但这更多是分子病理学家的研究领域，而非遗传咨询师的领域。
An incorrect amount of genetic material carried by the conceptus disturbs and distorts its normal growth pattern (from zygote → blastocyst → embryo → fetus).概念体携带的遗传物质数量异常会干扰并扭曲其正常生长模式（从受精卵→囊胚→胚胎→胎儿）。
In trisomy, there is three of a particular chromosome, instead of the normal two.在三体综合征中，特定染色体有三条，而不是正常的两条。
In monosomy, only one member of the pair is present.在单体性中，该对染色体中仅有一条存在。
Two of each is the only combination that works properly!两个各一个才是唯一能正常运作的组合！
It is scarcely surprising that a process as exquisitely complex as the development of the human form should be vulnerable to a confused outflow of genetic instruction from a nucleus with a redundant or incomplete database.一个像人类形态发育这样极其复杂的过程，很容易因细胞核中冗余或不完整的数据库导致基因指令混乱输出，这几乎不足为奇。
Trisomy and monosomy for a whole chromosome were the first cytogenetic mechanisms leading to an abnormal phenotype to be identified.整条染色体的三体和单体是导致异常表型被识别的最早细胞遗传学机制。
More fully, we can list the following pathogenetic mechanisms that arise from chromosomal abnormalities: 1.更全面地，我们可以列出以下由染色体异常引起的发病机制：1.
A dosage effect, with a lack (deletion) or excess (duplication) of chromosomal material, whether for a whole chromosome or a part of a chromosome.剂量效应，即染色体物质的缺失（缺失）或过量（重复），无论是针对整条染色体还是染色体的一部分。
This is by far the predominant category. 2.这是迄今为止最主要的一类。
A direct damaging effect, with disruption of a gene at the breakpoint of a rearrangement. 3.一种直接的破坏性效应，在重排的断裂点处破坏一个基因。
A position effect, whereby a gene in a new chromosomal environment functions inappropriately. 4.位置效应，即基因在新的染色体环境中功能异常。
An effect due to the incongruent parental origin of a chromosome or chromosomal segment (genomic imprinting). 5.由于染色体或染色体片段亲本来源不一致而产生的效应（基因组印记）。
Combinations of the above.以上各项的组合。
We discuss these mechanisms in more detail in following chapters.我们在后续章节中更详细地讨论这些机制。
Figure 1–5.图1–5。
The Spatial Arrangement of Chromosomes within the Nucleus.细胞核内染色体的空间排列。
Notes: The color coding indicates which part of the nucleus each chromosome occupies, in a human fibroblast.注释：颜色编码表示在人类成纤维细胞中，每条染色体占据细胞核的哪个部分。
The figure at left is a composite from the analysis of all 23 chromosomes.左侧图像是对全部23条染色体进行分析后合成的结果。
At right, chromosome 3’s territory is outlined, which can be discerned in the green coloring in the composite image.右侧图中标出了3号染色体的区域，在合成图像中可通过绿色着色辨认。
This study is based on expansion in situ genome sequencing (ExIGS).本研究基于原位扩增基因组测序（ExIGS）。
Source: From AS Labade et al., Expansion in situ genome sequencing links nuclear abnormalities to hotspots of aberrant euchromatin repression, bioRχiv 2024.09.24.614614, 2024.来源：摘自AS Labade等人，《原位扩增基因组测序将核异常与异常常染色质抑制热点联系起来》，bioRχiv 2024.09.24.614614，2024年。
Courtesy of JD Buenrostro and Colleagues, and with their permission.经JD Buenrostro及其同事惠允并获其许可。
4 AUTOSOMAL IMBALANCE
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10 BASIC CONCEPTS AUTOSOMAL IMBALANCE As noted earlier, imbalance may involve the gain or loss of a whole chromosome—full aneuploidy—or of part of a chromosome—partial aneuploidy.10 基本概念 常染色体失衡 如前所述，失衡可能涉及整条染色体的获得或丢失——完全非整倍体——或部分染色体的获得或丢失——部分非整倍体。
Full aneuploidies are trisomies and monosomies; partial aneuploidies are duplications (dup) and deletions (del).完全非整倍体包括三体和单体；部分非整倍体包括重复（dup）和缺失（del）。
The abnormality may occur in the non-mosaic or mosaic state.异常可能以非嵌合或嵌合状态出现。
Loss (that is, monosomy/deletion) of chromosomal material typically has a more devastating effect on growth of the conceptus than does an excess of material (that is, trisomy/duplication).染色体物质的丢失（即单体/缺失）通常对胚胎生长的影响比物质过量（即三体/重复）更具破坏性。
Smaller dups and dels are referred to as copy number variants (CNVs), and Collins et al. (2022) document, at the level of individual dosage-sensitive genes within the CNV segments, which loci are critical to the generation of phenotypic abnormality; they speak of haploinsufficient (deletion intolerance) and triplosensitive (duplication intolerance) imbalance.较小的重复和缺失被称为拷贝数变异（CNV），Collins等人（2022年）在CNV片段内单个剂量敏感基因的水平上，记录了哪些位点对产生表型异常至关重要；他们提到了单倍剂量不足（缺失不耐受）和三倍敏感（重复不耐受）失衡。
Certain imbalances lead to certain abnormal phenotypes.某些失衡会导致某些异常表型。
The spectrum is listed in outline in Box 1–1.该谱系在框1–1中概要列出。
Most full autosomal trisomies and virtually all full autosomal monosomies set development of the conceptus so awry that, sooner or later, abortion occurs—the embryo “self-destructs” and is expelled from the uterus.大多数完全常染色体三体和几乎所有完全常染色体单体都会严重扰乱胚胎发育，以至于迟早会发生流产——胚胎“自我毁灭”并被排出子宫。
This issue is further explored in Chapter 20.这一问题将在第20章进一步探讨。
A few full trisomies are not necessarily lethal in utero, and many partial chromosomal aneuploidies are associated with survival through to the birth of an infant.少数完全三体在子宫内不一定致命，而许多部分染色体非整倍体与婴儿存活至出生相关。
Characteristically, “survivable imbalances” produce a phenotype of widespread dysmorphogenesis, and there may be malformation of internal organs and limbs.典型情况下，“可存活的失衡”会产生广泛形态发生异常的表型，并可能伴有内脏器官和四肢畸形。
It is often in the facial appearance (facies) that the most recognizable physical abnormality is seen, with Down syndrome the classic example, although the physical phenotype in Box 1–1.最易识别的身体异常往往体现在面部外观上，唐氏综合征是典型例子，尽管框1–1中列出的身体表型……
The Spectrum of Effects, in Broad Outline, Resulting from Constitutional Chromosomal Abnormality 1.染色体结构异常所致效应的总体轮廓 1.
Devastation of blastogenesis, with transient implantation or non-implantation of the conceptus. 2.胚细胞发育的毁灭性破坏，导致胚胎短暂着床或未着床。 2.
Devastation of embryogenesis, with spontaneous abortion, usually in the first trimester. 3.胚胎发生的毁灭性破坏，导致自然流产，通常发生在孕早期。 3.
Major disruption of normal intrauterine morphogenesis, with second or third trimester abortion/fetal death in utero, stillbirth, or early neonatal death. 4.正常宫内形态发生的主要障碍，导致孕中期或晚期流产/宫内胎儿死亡、死产或早期新生儿死亡。 4.
Major disruption of normal intrauterine morphogenesis, but with some extrauterine survival. 5.正常宫内形态发生的主要障碍，但存在一定宫外存活能力。 5.
Moderate distortion of normal intrauterine development, with substantial extrauterine survival and severe intellectual disability. 6.正常宫内发育的中度扭曲，具有较高宫外存活率但伴有严重智力障碍。 6.
Mild distortion of normal intrauterine development, with substantial extrauterine survival and considerable intellectual compromise. 7.正常宫内发育的轻度扭曲，具有较高宫外存活率但伴有显著智力缺陷。 7.
Minimal physical phenotypic effect, varying degrees of intellectual compromise; possible compromise of fertility. 8.极轻微的身体表型效应，不同程度的智力缺陷；可能影响生育能力。 8.
No discernible physical phenotypic effect; cognitive function within the normal range, but less than expected from the family background.无明显身体表型效应；认知功能在正常范围内，但低于家庭背景预期水平。
5 SEX CHROMOSOMAL ABNORMALITY
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Elements of Medical Cytogenetics 11 some cases of subtler deletion or duplication may be rather “bland.” The most complex organ of all, the brain, is the most vulnerable to a less-than-optimal genetic constitution, and some compromise of mental and intellectual functioning, usually to the extent of an obvious deficit, is nearly invariable, at least in imbalances of classical size.医学细胞遗传学要素 11 某些微缺失或微重复病例可能表现“温和”。最复杂的器官——大脑，对欠佳的遗传构成最为敏感，精神与智力功能的某种缺陷（通常表现为明显障碍）几乎不可避免，至少在经典大小的染色体失衡中如此。
With several of the (much smaller) imbalances due to copy number variants, flawed neurodevelopmental progress or intellectual disability,6 with an outwardly normal physical phenotype, is well recognized as a chromosomal presentation.对于由拷贝数变异引起的若干（更小）失衡，伴有外观正常身体表型的神经发育缺陷或智力障碍6已被公认为染色体异常的表现形式。
Thus, the central concern of most people seeking genetic counseling for a chromosomal condition is that of having a child who might have a physical, intellectual, or severe social handicap.因此，大多数因染色体疾病寻求遗传咨询的人的核心担忧，是可能生育出存在身体、智力或严重社会障碍的孩子。
Historically, the chromosomal basis of many syndromes was identified following analysis of groups of patients with similar phenotypes.历史上，许多综合征的染色体基础是通过分析具有相似表型的患者群体而确定的。
This “phenotype-first” approach led to the identification of many of the well-known microdeletion syndromes (and of course such classic conditions as Down syndrome).这种“表型优先”方法导致了许多知名微缺失综合征（当然也包括唐氏综合征等经典疾病）的发现。
With the advent of molecular karyotyping, new syndromes came to be identified based on their DNA aberration, a “genotype-first” approach.随着分子核型分析的出现，新综合征开始基于其DNA异常被识别，即“基因型优先”方法。
Representative examples of these newer syndromes are reviewed in Chapter 14.这些较新综合征的代表性案例将在第14章中讨论。
SEX CHROMOSOMAL ABNORMALITY Sex chromosome (gonosome) imbalance has a much less deleterious effect on the phenotype than does autosomal aneuploidy.性染色体异常 性染色体（性染色体）失衡对表型的有害影响远小于常染色体非整倍体。
The X chromosome is one of the larger and is gene-dense; the Y is small, comprising mostly heterochromatin, and carries very few genes (the key one being SRY, which determines maleness).X染色体较大且基因密集；Y染色体较小，主要由异染色质组成，携带极少量基因（关键基因为SRY，决定男性性别）。
In both male and female, one, and only one, completely functioning X chromosome is needed.无论男性还是女性，都需要且仅需要一个完全功能的X染色体。
X chromosomes in excess of one are inactivated, as the normal 46,XX female exemplifies; her second X does, however, maintain some segments genetically active.多余的X染色体被失活，正如正常46,XX女性所示；然而，她的第二条X染色体确实保持部分基因活性。
With X chromosome excess or deficiency, a partially successful buffering mechanism exists whereby the imbalance is counteracted, in an attempt to achieve the same effect as having a single active X.在X染色体过多或过少的情况下，存在一种部分有效的缓冲机制，用以抵消这种不平衡，从而试图达到与仅有一条活性X染色体相同的效果。
In such states as, for example, XXX, XXY, XXXX, XXYY, and XXXXX, excess X chromosomes are inactivated.例如，在XXX、XXY、XXXX、XXYY和XXXXX等状态下，多余的X染色体被失活。
In the 45,X state, the single X remaining is not subject to inactivation.在45,X状态下，唯一剩余的X染色体不会失活。
If an abnormal X chromosome (e.g., an isochromosome, or a deleted X) is present, then, as a rule, cells containing this abnormal chromosome as the active X are selected against, perhaps due to preferential growth of those cells in which it is the normal X that is the active one.如果存在异常的X染色体（例如等臂染色体或缺失的X染色体），那么通常情况下，含有该异常染色体作为活性X染色体的细胞会受到选择抑制，这可能是由于那些以正常X染色体为活性X染色体的细胞具有优先生长优势。
In X imbalance, the reproductive tract and brain are the organs predominantly affected.在X失衡中，生殖道和大脑是主要受影响的器官。
The effect may be minimal.效果可能微乎其微。
As for Y chromosome excess, such as XYY, there is a limited phenotypic consequence—but again, the brain may be a vulnerable organ. 6 Words can be powerful, and choice of language can help, or hinder, a counseling consultation: Facts are to be conveyed clearly but also sensitively.关于Y染色体过多（如XYY综合征），其表型影响有限——但大脑仍可能是易受影响的器官。
The term “mental retardation,” once widespread in the genetics literature, has acquired a pejorative and somewhat harsh sense over the years, and we now prefer such expressions as “intellectual disability” or “cognitive impairment.” “Developmental delay” is a widely used term, and it can be perfectly appropriate in early childhood setting, but less so in dealing with a school-age child or adult; this distinction acknowledges that prediction of intellectual capacity is more precise in older children.“智力迟钝”这一术语曾广泛出现在遗传学文献中，但多年来已带有贬义且略显刺耳，如今我们更倾向于使用“智力障碍”或“认知损伤”等表述。“发育迟缓”是一个广泛使用的术语，在幼儿阶段完全适用，但在涉及学龄儿童或成人时则不太恰当；这一区分承认了年龄较大的儿童智力能力的预测更为精确。
As we write elsewhere, counselors will need to know to whom they speak, and what language is best to use.正如我们在别处所写，咨询师需要了解他们与谁交谈，以及使用何种语言最为合适。
6 THE FREQUENCY AND IMPACT OF CYTOGENETIC PATHOLOGY
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12 BASIC CONCEPTS Functional Imbalance A correct amount of chromatin does not necessarily mean the phenotype will be normal.12 基本概念 功能失衡 染色质的正确数量并不一定意味着表型正常。
Inappropriate inactivation, or activation, of a segment of the genome can compromise the genetic message.基因组某一片段的不适当失活或激活，可能会损害遗传信息。
Some segments of the genome require only monosomic expression, and the homologous segment on the other chromosome is inactivated.基因组的一些片段只需要单倍体表达，而另一条染色体上的同源片段则被失活。
If this control fails, both segments can become activated or both inactivated, and the over- or under-expression of the contained loci can cause phenotypic abnormality.如果这一控制失效，两个区段可能同时被激活或同时失活，其中所含基因座的过度表达或表达不足可能导致表型异常。
The classic example of this is genomic imprinting according to parent of origin, and we discuss this concept in Chapter 19.这方面的经典例子是根据亲本来源的基因组印记，我们在第19章讨论这一概念。
A rather specialized example arises with the X-autosome translocation.一个相当特殊的例子出现在X-常染色体易位中。
A segment of X chromosome can fail to be inactivated or, conversely, X-inactivation can spread into an autosomal segment, and in each case to deleterious effect (Chapter 6).X染色体的一段可能无法被失活，或者相反，X失活可能扩散到常染色体片段中，这两种情况都会产生有害效应（第6章）。
THE FREQUENCY AND IMPACT OF CYTOGENETIC PATHOLOGY According to the window of observation (Figure 1–6), chromosomal disorders make a greater or lesser contribution to human mortality and morbidity.细胞遗传病理学的频率与影响 根据观察窗口（图1-6），染色体疾病对人类死亡率和发病率的影响程度不一。
Looking at prenatal existence, the earliest window has been provided by the in vitro fertilization (IVF) clinic, from the procedure of preimplantation genetic testing (Chapter 23), at which cells taken from 5-day-old embryos are subjected to genetic analysis, and an extraordinary fraction are chromosomally abnormal.观察产前存在状态，最早的时间窗口由体外受精（IVF）诊所提供，即通过植入前遗传学检测（第23章）程序，从5天大的胚胎中提取细胞进行基因分析，其中异常高比例的细胞存在染色体异常。
After implantation (about day 6), and through the first trimester of pregnancy (to week 13), chromosomal mortality is very high, and aneuploidy is the major single cause of spontaneous abortion (Chapter 20).植入后（约第6天）至妊娠早期（第13周），染色体致死率极高，非整倍体是自然流产的主要单一原因（第20章）。
Perinatal and early infant death have a significant chromosomal component, of which trisomies 18 and 21 (although the latter less so in more recent times) are major elements.围产期和婴儿早期死亡中染色体因素占比显著，其中18三体和21三体（尽管近年来后者影响较小）是主要因素。
In Table 1–2 we set out the birth incidences of the various categories of (classical) chromosomal abnormality; these data are from a Danish study, one of a number that have examined this question in the later decades of the 20th century with largely similar findings in each.表1–2列出了各类（经典）染色体异常的出生发生率；这些数据来自一项丹麦研究，该研究是20世纪后期多个探讨此问题且结果大致相似的研究之一。
Overall, around one in 135 liveborn babies have a classical chromosomal abnormality, and about 40% of these are phenotypically abnormal due to the chromosome defect.总体而言，约每135名活产婴儿中就有1名存在经典染色体异常，其中约40%因染色体缺陷而表型异常。
Figure 1–6.图1–6。
The windows of observation open to chromosomal study.染色体研究可观察的窗口期。
Note: Obviously, time on the x axis is depicted asymmetrically.注：显然，x轴上的时间呈不对称描绘。
FDIU, fetal death in utero.FDIU，宫内胎儿死亡。
Elements of Medical Cytogenetics 13 (continued) Table 1–2.医学细胞遗传学要素 13（续）表1–2。
Classical Chromosomal Rearrangements and Imbalances, Recorded in 34,910 Live Newborns in Århus, Denmark, Over a Total 13-Year Period, 1969–1974 and 1980–1988 NO.丹麦奥胡斯市在1969–1974年及1980–1988年共13年期间，34,910名活产新生儿中记录的经典染色体重排与失衡 编号。
OF CASES PER 1,000a BIRTH FREQUENCY PER GROUP Sex Chromosomes Klinefelter Syndrome and Variants 47,XXY 20 1.12b 47,XXY/46,XY 7 0.39 46,XX ♂ 2 0.11 1 in 616 ♂ XYY 47,XYY 18 1.01 47,XYY/46,XY 2 0.11 1 in 894 ♂ XXX 47,XXX 17 1.00 1 in 1,002 ♀ Turner Syndrome and Variants 45,X 1 0.06 45,X/46,XX and 45,X/47,XXX 3 0.18 45,X/46,X,r(X) 1 0.06 45,X/46,X,i(Xq)/47,X,i(Xq),i(Xq) 1 0.06 Other Turner Variant 2 0.12 1 in 2,130 ♀ Other 45,X/46,XY 1 0.06 46,XX/47,XX,del(Yq) 1 0.06 46,XX/46,XY 1 0.06 Total 77 2.21 1 in 453 Autosomes Unbalanced Forms Trisomy 13 2 0.06 Trisomy 18 7 0.20 Trisomy 21 51 1.46 Trisomy 8 1 0.03 Supernumerary marker, ring 25 0.72 Deletions, duplications 6 0.17 1 in 379 Balanced Forms Robertsonian 13/14 translocation 34 0.97 Other Robertsonian 9 0.26 Reciprocal translocations 50 1.43 Inversions (other than of chromosome 2) 4 0.11 1 in 360 14 BASIC CONCEPTS The finer the cytogenetic focus, the greater the incidence, and it is now a task for the cytogenetic (or molecular genomic) epidemiologist of this century, in the microarray/molecular era, to derive new estimates of cytogenetic abnormalities in the different populations (Rosenfeld et al. 2013).每1,000例中的病例数a 每组出生频率 性染色体 克兰费尔特综合征及其变异型 47,XXY 20 1.12b 47,XXY/46,XY 7 0.39 46,XX ♂ 2 0.11 每616名♂中1例 XYY 47,XYY 18 1.01 47,XYY/46,XY 2 0.11 每894名♂中1例 XXX 47,XXX 17 1.00 每1,002名♀中1例 特纳综合征及其变异型 45,X 1 0.06 45,X/46,XX 和 45,X/47,XXX 3 0.18 45,X/46,X,r(X) 1 0.06 45,X/46,X,i(Xq)/47,X,i(Xq),i(Xq) 1 0.06 其他特纳变异型 2 0.12 每2,130名♀中1例 其他 45,X/46,XY 1 0.06 46,XX/47,XX,del(Yq) 1 0.06 46,XX/46,XY 1 0.06 总计 77 2.21 每453例中1例 常染色体 非平衡型 13三体 2 0.06 18三体 7 0.20 21三体 51 1.46 8三体 1 0.03 额外标记、环状染色体 25 0.72 缺失、重复 6 0.17 每379例中1例 平衡型 罗伯逊易位13/14 34 0.97 其他罗伯逊易位 9 0.26 相互易位 50 1.43 倒位（2号染色体除外） 4 0.11 每360例中1例 14 基本概念 细胞遗传学聚焦越精细，发生率越高，本世纪（微阵列/分子时代）的细胞遗传学（或分子基因组学）流行病学家的任务，是得出不同人群中细胞遗传学异常的新估计值（Rosenfeld et al. 2013）。
While the incidence of classical data remains stable, the subtler del/dups have been increasingly observed in more recent years (Figure 1–7).尽管经典数据发生率保持稳定，但近年来更细微的缺失/重复被越来越多地观察到（图1–7）。
A useful start has been made by Smajlagić et al. (2021) in their analysis of a population of newborns and their parents, in whom they tested for the presence of 13 of the recurrent deletions and duplications that have become well recognized as causative of known phenotypes/syndromes and are associated, in particular, with a neurodevelopmental component.Smajlagić等人（2021）在其对新生儿及其父母人群的分析中取得了有益的开端，他们检测了13种复发性缺失和重复的存在，这些异常已被充分认为是已知表型/综合征的病因，尤其与神经发育成分相关。
They were able to make a distinction between those del/ dups inherited from a parent, and those arising de novo (Table 1–3).他们能够区分那些从父母遗传的缺失/重复与新生突变（表1–3）。
In this population, the notable figure of one in 200 children were born with a recurrent deletion or duplication; in other words, these abnormalities are not uncommon.在该人群中，每200名儿童中就有1名出生时携带复发性缺失或重复，换言之，这些异常并不罕见。
And if we combine the overall estimates of Tables 1–2 (1 in 207) and 1–3 (1 in 200), and if we may extrapolate these Scandinavian data more generally, we approach a broad figure that about one in 100 individuals, at least in a newborn population, are chromosomally imbalanced and with an associated abnormal phenotype, whether of severe, moderate, mild, or barely discernible degree.如果我们将表1–2（每207例中1例）和表1–3（每200例中1例）的总体估计值合并，并且如果我们可以更广泛地推断这些斯堪的纳维亚数据，我们大致接近一个宽泛的数字：约每100人中就有1人（至少在新生儿人群中）存在染色体失衡并伴有相关异常表型，程度从严重、中度、轻微到几乎难以察觉。
Adolescence is a period during which many sex chromosome defects come to light, when pubertal change fails to occur, and in young adulthood when chromosomal causes of infertility are recognized.青春期是许多性染色体缺陷显现的时期，此时青春期变化未能发生；而在青年期，染色体导致的不育问题被识别。
If the target population is fertile adults (ascertained incidentally), a much lower frequency of sex chromosome aneuploidy is observed (Samango-Sprouse et al. 2016).如果目标人群是育龄成人（偶然发现），观察到的性染色体非整倍体频率要低得多（Samango-Sprouse et al. 2016）。
If we were to study a population of 70-year-olds, we could expect to see very few individuals with an unbalanced autosomal karyotype (but loss of the Y chromosome is a common observation in older men; p. 472).如果我们研究一个70岁人群，可以预期看到极少数个体存在非平衡常染色体核型（但Y染色体丢失在老年男性中常见；第472页）。
NO.编号
OF CASES PER 1,000a BIRTH FREQUENCY PER GROUP Combined sex plus autosomal totals 266 7.62 1 in 131 Combined totals, excluding balanced autosomal forms 169 4.84 1 in 207 Notes: Not included in the 34,910 live newborns listing are four cases of induced abortion due to sex chromosome prenatal diagnosis, involving the karyotypes 47,XXY, 47,XYY, 47,XXX, and 45,X/46,X,del(Xq), and 15 cases of autosomal-diagnosis induced abortions, involving the karyotypes +21, +13, +18, and three different derivative chromosomes.每千例中的病例数
Had these pregnancies proceeded to term, the frequencies in the relevant group category would have been marginally increased.如果这些妊娠持续到足月，相关组别中的频率将略有增加。
These figures might continue to be broadly valid into this century, except that the category of deletions and duplications will substantially increase due to the more powerful detection now offered by molecular technology (Table 1–3). aPer 1,000 male, per 1,000 female, or per 1,000 both, as appropriate.这些数据在本世纪可能仍然大致有效，但缺失和重复类别的数量将大幅增加，因为分子技术如今提供了更强大的检测手段（表1-3）。a每1000名男性、每1000名女性或每1000名男女合计，视情况而定。
The gender-specific denominators in this study were 17,872 males and 17,038 females. bAn increasing incidence of XXY in recent years has been suggested, and an Australian study, including data up to 2006, arrived at a figure of 1.91 per 1,000 (Herlihy and Halliday 2008; Morris et al. 2008; Herlihy et al. 2010).本研究中的性别特异性分母为17,872名男性和17,038名女性。
Source: From Nielsen and Wohlert (1991) Table 1–2.源自Nielsen和Wohlert（1991）表1–2。
Continued继续
7 THE FREQUENCY AND IMPACT OF CYTOGENETIC PATHOLOGY
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Elements of Medical Cytogenetics 15 While few classic cytogenetic defects come to attention later in adult life, many children with an aneuploidy can survive well into adulthood and some into old age, and some require lifelong care from their families or from the state.医学细胞遗传学要素 15 尽管少数经典细胞遗传学缺陷在成年后期才引起注意，但许多患有非整倍体的儿童能够存活至成年，部分甚至活到老年，其中一些人需要家庭或国家提供终身照护。
This latter group imposes a considerable emotional and financial burden.后一组人承受着巨大的情感和经济负担。
While some parents and caregivers declare the emotional return they experience from looking after these individuals, for others this responsibility is a source of continuing, unresolved, if attenuated, grief.尽管一些父母和照护者宣称他们在照顾这些个体时获得了情感上的回报，但对其他人而言，这种责任却是一种持续、未解决、即便有所减轻的悲伤来源。
As for morbidity, the brain, as mentioned above, is the most vulnerable organ, and chromosomal defects are the basis of a substantial fraction of all intellectual deficit.关于发病率，如上所述，大脑是最脆弱的器官，而染色体缺陷是相当一部分智力缺陷的基础。
Many of these affected individuals will also have structural malformations that cause functional physical disability.这些受影响的个体中，许多人还会出现导致功能性身体残疾的结构畸形。
Among an intellectually disabled population, Down syndrome is the predominant contributor in the fraction who have a classic chromosome abnormality (Phelan et al. 1996).在智力障碍人群中，唐氏综合征是导致经典染色体异常的主要因素（Phelan et al. 1996）。
Development of the heart is particularly susceptible to chromosomal imbalance, and in a population study from the US National Center on Birth Defects, 1 in 8 infants with a congenital heart defect had a chromosomal abnormality with, again. trisomy 21 the most common of these (53%), followed by trisomy 18 (13%), 22q11.2 deletion (12%), and trisomy 13 (6%) (Hartman et al. 2011).心脏发育尤其易受染色体失衡影响，在美国国家出生缺陷中心的一项人群研究中，每8名先天性心脏缺陷婴儿中就有1名存在染色体异常，其中21三体综合征最为常见（占53%），其次为18三体综合征（13%）、22q11.2缺失（12%）和13三体综合征（6%）（Hartman等，2011年）。
Figure 1–7.图1–7。
The Increasing Detection of Deletions and Duplications.缺失与重复的检测日益增多。
Notes: Shown are the numbers (y-axis) of terminations in central Denmark over the period 2008–2021 (x-axis), for the indications of an aneuploidy (upper line), and for a deletion or duplication (lower line).图中显示的是2008–2021年期间（x轴）丹麦中部终止妊娠的数量（y轴），分别针对非整倍体（上方线条）以及缺失或重复（下方线条）的指征。
The baseline birth rate in this population is c. 14,000 per annum.该人群的基线出生率约为每年14,000例。
Termination on the grounds of a fetal abnormality was available from 12 to 22 weeks gestation, but required approval from a local Regional Abortion Council.因胎儿异常而终止妊娠可在孕12至22周内进行，但需获得当地区域堕胎委员会的批准。
Source: From L Raaby et al., Has the introduction of increased genetic prenatal testing affected rates of termination of pregnancy due to fetal abnormality?从L·拉比等人所著《基因产前检测的增加是否影响了因胎儿异常而终止妊娠的比例？》
Prenat Diagn 44:280–288, 2024.产前诊断 44:280–288, 2024。
Courtesy L Raaby, and with the permission of John Wiley & Sons.承蒙L·拉比惠允，并经约翰·威利父子出版公司许可。
Table 1–3.表1–3。
The Population Prevalences of Some of the More Notable Deletions and Duplications, Derived from the Norwegian Mother, Father, and Child Cohort Study, 1999–2008 RECURRENT CNVs DE NOVO CNVs ALL CNVs Position (hg38) Del/Dup N Parental N Prevalence 1:147,107,276-147,924,476 del1q21.1 distal 2 pat ×2 6 4.9 1:147,107,276-147,924,476 dup1q21.1 distal 0 4 3.26 3:196,033,055-197,619,681 del3q29 1 pat 1 0.82 3:196,033,055-197,619,681 dup3q29 0 0 0 7:73,331,825-74,731,095 del7q11.23 (Williams-Beuren) 0 0 0 7:73,331,825-74,731,095 dup7q11.23 0 0 0 15:23,123,715-28,325,372 del15q11.2-13.1 (Prader-Willi/Angelman) 0 0 0 15:23,123,715-28,325,372 del15q11.2-13.1 2 mat ×2 3 2.450 15:30,783,588-32,154,652 del15q13.3 1 pat 5 4.08 15:30,783,588-32,154,652 dup15q13.3 1 pat 6 4.9 16:28,811,768-29,035,413 del16p11.2 distal 1 mat 3 2.45 16:28,811,768-29,035,413 dup16p11.2 distal 2 mat 8 6.53 16:29,639,423-30,183,727 del16p11.2 proximal 4 mat ×3, pat 6 4.9 16:29,639,423-30,183,727 dup16p11.2 proximal 0 5 4.08 17:1,344,540-2,685,615 del17p13.3 (Miller-Dieker) 0 0 0 17:1,344,540-2,685,615 dup17p13.3 0 0 0 17:16,908,429-20,313,519 del17p11.2 (Smith-Magenis) 0 0 0 17:16,908,429-20,313,519 dup17p11.2 (Potocki-Lupski) 0 0 0 17:36,460,758-37,856,053 del17q12 3 mat, pat ×2 3 2.45 17:36,460,758-37,856,053 dup17q12 0 2 1.63 17:45,628,753-46,087,790 del17q21.31 (Koolen-deVries) 0 0 0 17:45,628,753-46,087,790 dup17q21.31 0 0 0 22:19,037,347-21,114,846 del22q11.2 (DiGeorge) 1 mat 1 0.82 22:19,037,347-21,114,846 dup22q11.2 2 mat, pat 6 4.9 22:21,566,197-23,310,015 del22q11.2 distal 0 0 0 22:21,566,197-23,310,015 dup22q11.2 distal 0 0 0 Total 20 16/10,000 59 48/10,000 Notes: The extents of the del/dups are shown in molecular detail, at the level of the nucleotide. “hg38” refers to Human Genome build, version 38, also referred to as GRCh38 (Genome Reference Consortium human build 38).来自挪威母亲、父亲和儿童队列研究（1999–2008）的一些较显著缺失和重复的人群患病率 复发性CNV 新发CNV 所有CNV 位置（hg38） 缺失/重复 亲本来源 数量 患病率（每万人） 1:147,107,276-147,924,476 缺失1q21.1远端 2 父源×2 6 4.9 1:147,107,276-147,924,476 重复1q21.1远端 0 4 3.26 3:196,033,055-197,619,681 缺失3q29 1 父源 1 0.82 3:196,033,055-197,619,681 重复3q29 0 0 0 7:73,331,825-74,731,095 缺失7q11.23（威廉姆斯-伯伦综合征） 0 0 0 7:73,331,825-74,731,095 重复7q11.23 0 0 0 15:23,123,715-28,325,372 缺失15q11.2-13.1（普拉德-威利/安格尔曼综合征） 0 0 0 15:23,123,715-28,325,372 缺失15q11.2-13.1 2 母源×2 3 2.45 15:30,783,588-32,154,652 缺失15q13.3 1 父源 5 4.08 15:30,783,588-32,154,652 重复15q13.3 1 父源 6 4.9 16:28,811,768-29,035,413 缺失16p11.2远端 1 母源 3 2.45 16:28,811,768-29,035,413 重复16p11.2远端 2 母源 8 6.53 16:29,639,423-30,183,727 缺失16p11.2近端 4 母源×3、父源 6 4.9 16:29,639,423-30,183,727 重复16p11.2近端 0 5 4.08 17:1,344,540-2,685,615 缺失17p13.3（米勒-迪克综合征） 0 0 0 17:1,344,540-2,685,615 重复17p13.3 0 0 0 17:16,908,429-20,313,519 缺失17p11.2（史密斯-马吉利综合征） 0 0 0 17:16,908,429-20,313,519 重复17p11.2（波托茨基-卢普斯基综合征） 0 0 0 17:36,460,758-37,856,053 缺失17q12 3 母源、父源×2 3 2.45 17:36,460,758-37,856,053 重复17q12 0 2 1.63 17:45,628,753-46,087,790 缺失17q21.31（库伦-德弗里斯综合征） 0 0 0 17:45,628,753-46,087,790 重复17q21.31 0 0 0 22:19,037,347-21,114,846 缺失22q11.2（迪乔治综合征） 1 母源 1 0.82 22:19,037,347-21,114,846 重复22q11.2 2 母源、父源 6 4.9 22:21,566,197-23,310,015 缺失22q11.2远端 0 0 0 22:21,566,197-23,310,015 重复22q11.2远端 0 0 0 总计 20 16/10,000 59 48/10,000 注：缺失/重复的范围以核苷酸水平的分子细节显示。“hg38”指人类基因组版本38，也称为GRCh38（基因组参考联盟人类构建版本38）。
Prevalences are per 10,000.患病率以每万人计。
The study was based upon a material of 12,252 newborns and their parents.该研究基于12,252名新生儿及其父母的数据。
Source: From Smajlagić et al., Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents, Eur J Hum Genet, 29:205–215, 2021.来自Smajlagić等人的研究，《12,252名新生儿及其父母中与神经发育障碍相关的复发性拷贝数变异的人群患病率及遗传模式》，载于《欧洲人类遗传学杂志》，第29卷，第205–215页，2021年。
8 THE FREQUENCY AND IMPACT OF CYTOGENETIC PATHOLOGY
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Elements of Medical Cytogenetics 17 The Research Application of Cytogenetic Pathology The phenotypes that result from chromosome abnormalities can point the way to discovery of the causative genes.医学细胞遗传学要素 17 细胞遗传病理学的研究应用 染色体异常导致的表型可为发现致病基因指明方向。
An early example of deletion mapping is the recognition that the gene for retinoblastoma was on chromosome 13, given the association of this cancer with the 13q– syndrome.缺失定位法的一个早期例子是，根据视网膜母细胞瘤与13q–综合征的关联，发现该癌症的基因位于13号染色体上。
Another cancer gene to be similarly mapped was APC (adenomatous polyposis coli), following the observation of polyposis of the colon in an individual with intellectual disability and del(5)(q22q23) (Hockey et al. 1989).另一个类似定位的癌症基因是APC（腺瘤性结肠息肉病），其依据是在一名智力障碍且携带del(5)(q22q23)的个体中观察到结肠息肉病（Hockey et al. 1989）。
The triple dose of chromosome 21 in Down syndrome (DS), and knowing that Alzheimer disease almost invariably affects DS persons aged 40 and older (Hithersay et al. 2019), was a signpost on the way to finding the β-amyloid precursor protein (APP) gene as one of the major Alzheimer loci; and the DS adult population may prove a valuable resource in the assessment of new dementia treatments (Rafii and Fortea 2023).唐氏综合征（DS）患者体内存在三倍量的21号染色体，且已知阿尔茨海默病几乎不可避免地影响40岁及以上的DS患者（Hithersay等，2019），这为发现β-淀粉样前体蛋白（APP）基因是阿尔茨海默病主要位点之一指明了方向；而DS成年人群可能成为评估新型痴呆治疗方法的重要资源（Rafii和Fortea，2023）。
A translocation with one breakpoint at 7q11.23 was found to disrupt the elastin gene in a family segregating supravalvular aortic stenosis.在一例家族性主动脉瓣上狭窄的病例中，发现一个断裂点位于7q11.23的易位破坏了弹性蛋白基因。
Further investigation of this locus in Williams syndrome proved this to be the site of deletion in this condition (Nickerson et al. 1995).对威廉姆斯综合征中这一位点的进一步研究证实，该位点正是该病症中缺失的位置（Nickerson等人，1995年）。
The gene for CHARGE7 syndrome, CHD7, was discovered due to two patients with an 8q12 microdeletion (Vissers et al. 2004).CHARGE7综合征的基因CHD7是由于两名8q12微缺失患者而被发现的（Vissers等人，2004年）。
David et al. (2023) studied two men presenting with infertility, of otherwise normal phenotype, in whom a balanced chromosome rearrangement had been identified: t(5;9)(q32;p21.1) and t(4;21) (p15.1;q22.3), respectively, leading them to propose YIPF5 near the 5q32 breakpoint, and SPATC1L within 21q23 as candidates contributory to the control of spermatogenesis.David等人（2023）研究了两名表现为不育但其他表型正常的男性，他们分别被鉴定出存在平衡染色体重排：t(5;9)(q32;p21.1)和t(4;21)(p15.1;q22.3)，这促使他们提出位于5q32断点附近的YIPF5基因以及21q23内的SPATC1L基因可能是参与精子发生调控的候选基因。
We have conducted reviews of chromosomal conditions in which epilepsy and kidney disease are features, with the aim of providing leads to epilepsy genes and renal genes (Singh et al. 2002a; Amor et al. 2003).我们对以癫痫和肾脏疾病为特征的染色体疾病进行了综述，旨在为癫痫基因和肾脏基因的研究提供线索（Singh 等，2002a；Amor 等，2003）。
The precision of microarray analysis, coupled with access to genome databases, now allows a much finer focus in the pursuit of causative genes.微阵列分析的精确性，加上基因组数据库的获取，如今使得在寻找致病基因时能够实现更精细的聚焦。
Ou et al. (2008) proposed, and Ballesta-Martínez et al. (2013) supported, that one of the genes SIX1, SIX6, or OTX2 might be the basis of one form of branchio-oto-renal syndrome, from their study of a child with a duplication of 14q22.3q23.3; SIX1 was eventually revealed as the culprit gene.Ou等人(2008)提出，且Ballesta-Martínez等人(2013)支持，SIX1、SIX6或OTX2基因之一可能是某种鳃-耳-肾综合征的基础，这一结论源于他们对一名携带14q22.3q23.3重复的患儿的研究；最终SIX1被证实为致病基因。
We have shown WDR35 to be the gene for a short rib–polydactyly syndrome, having found a microdeletion on chromosome 2p24 by single nucleotide polymorphism (SNP) and copy number variant (CNV) analysis (Mill et al. 2011); and RAB39B was found to be the basis of a syndrome of early-onset Parkinson disease and intellectual disability, a 45 kb deletion at Xq28 leading us to this discovery (Wilson et al. 2014).我们通过单核苷酸多态性（SNP）和拷贝数变异（CNV）分析发现染色体2p24上的微缺失，从而证明WDR35是一种短肋-多指（趾）综合征的致病基因（Mill等，2011）；而RAB39B被发现是早发性帕金森病伴智力障碍综合征的基础，Xq28处一个45 kb的缺失引导我们得出这一发现（Wilson等，2014）。
It is a general principle that many important scientific discoveries are made serendipitously—or, as Louis Pasteur put it, “chance favors the prepared mind” (le hasard ne favorise que les esprits préparés).许多重要的科学发现都是偶然做出的，这是一条普遍规律——正如路易·巴斯德所言，“机遇只青睐有准备的头脑”。
Voullaire et al. (1993) identified a small supernumerary marker chromosome (sSMC) in a child with a nonspecific picture of physical abnormality and intellectual deficit, which had no C-band positive centromere 7 CHARGE = coloboma, heart, choanal atresia, retardation, genital, ear. 18 BASIC CONCEPTS (only a constriction).Voullaire等人（1993）在一名表现为非特异性身体异常和智力缺陷的儿童中发现了一个小型额外标记染色体（sSMC），该染色体没有C带阳性的着丝粒（仅有一个缢痕）。
Conventional wisdom has it (and indeed, as we have written above) that a chromosome cannot be stably transmitted at cell division if it has no centromere.传统观点认为（事实上，正如我们上文所述），没有着丝粒的染色体在细胞分裂时无法稳定传递。
These workers studied this sSMC and discovered that it did have a simple, but nevertheless functional, centromere.这些研究人员研究了这种sSMC，发现它确实拥有一个简单但功能正常的着丝粒。
This observation led the way to the delineation of the “neocentromere” (p. 319).这一观察结果引领了“新着丝粒”的界定（第319页）。

2 Chapter 2

9 CLASSICAL CYTOGENETIC ANALYSIS
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2 CHROMOSOME ANALYSIS FOR THE FIRST HALF-CENTURY of clinical cytogenetics, analysis of chromosomes was an exercise in microscopy.2 染色体分析 在临床细胞遗传学的头半个世纪中，染色体分析是一项显微镜操作。
This century, molecular methodologies are holding sway.本世纪，分子方法占据主导地位。
But it behooves the counselor to have a good understanding of how things used to be, not least because one often needs to make reference to the historical literature.但咨询师有必要充分了解过去的方法，尤其是因为常常需要参考历史文献。
And it is, of course, an obligation to keep abreast of new developments.当然，紧跟新进展也是一项义务。
Modern cytogenomic (this word now entering the lexicon) reports are sophisticated documents, and those who read them, and who interpret them to patients and families, need to be well informed.现代细胞基因组学（这个词正进入词汇库）报告是复杂的文件，阅读这些报告并向患者及其家属解释的人需要具备充分的知识。
CLASSICAL CYTOGENETIC ANALYSIS In classical methodology, chromosomes are analyzed under the light microscope, at a magnification of about 1000×.经典细胞遗传学分析 在经典方法中，染色体在光学显微镜下以约1000倍放大率进行分析。
The chromosomes are stained to be visible, and a great many staining techniques were used to demonstrate different features of the chromosome.染色体经过染色以便观察，大量染色技术被用于展示染色体的不同特征。
We list some of these, in particular those with a more immediate practical application to the clinical issues we discuss in this book, or which are of historical value when referring to the older literature.我们列出其中一些，特别是那些对我们本书讨论的临床问题有更直接实际应用的技术，或是在参考较旧文献时具有历史价值的技术。
Plain staining (“solid staining”).普通染色（“实心染色”）。
Many histologic dyes, including Giemsa, orcein, and Leishman, stained chromosomes uniformly.许多组织学染料，包括吉姆萨、地衣红和利什曼，都能均匀地染色染色体。
Until the early 1970s, these were the only stains available.直到20世纪70年代初，这些是唯一可用的染料。
Giemsa or G-banding.吉姆萨或G显带。
This procedure required a trypsin (protein digestion) step, and is the main staining method in use in routine classical cytogenetics.该过程需要胰蛋白酶（蛋白质消化）步骤，是常规经典细胞遗传学中使用的主要染色方法。
It allows for precise identification of every chromosome, and for the detection and delineation of structural abnormalities.它能够精确识别每条染色体，并检测和界定结构异常。
At the 400–550 band level, rearrangements down to about 5 megabases in length can be discerned, at least in regions where the banding pattern is distinctive.在400–550条带水平下，可以辨别长度约5兆碱基的重排，至少在条带模式独特的区域如此。
Its precision is increased by manipulations designed to arrest the chromosome in its more elongated state at early metaphase or prometaphase— high-resolution banding.其精确性通过旨在使染色体在早期中期或前中期更延展状态时被捕获的操作得以提高——即高分辨显带。
Alternative methods to demonstrate essentially the same morphology are quinacrine, or Q-banding, and reverse or R-banding.展示基本相同形态的替代方法有喹吖因显带（Q显带）以及反式显带（R显带）。
In R-banded chromosomes, the pale staining regions seen in G-banding stain darkly, and vice versa.在R显带染色体中，G显带中浅染的区域呈深染，反之亦然。
Constitutive or C-banding.组成性显带（C显带）。
This technique stains constitutive heterochromatin— mainly the centromeric heterochromatin, some of the material on the short arms of the acrocentric chromosomes, and the distal part of the long arm of the Y chromosome.该技术染色组成性异染色质——主要是着丝粒异染色质、近端着丝粒染色体短臂上的部分物质以及Y染色体长臂远端部分。
Constitutive heterochromatin, by definition, has no direct phenotypic effect and, in general, is devoid of active genes.组成性异染色质按定义无直接表型效应，通常不含活性基因。
Replication Banding.复制显带。
This technique is used primarily to identify inactive X chromatin.该技术主要用于识别失活的X染色质。
A nucleotide analog (BrdU) is added either as a pulse at the beginning, or在细胞周期开始时或结束时脉冲式加入核苷酸类似物（BrdU），
10 CHROMOSOMAL MICROARRAY ANALYSIS
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20 BASIC CONCEPTS toward the end of the cell cycle, to allow the cytogenetic distinction between chromatin that replicates early from that which replicates late.20 基本概念 以区分早期复制与晚期复制的染色质。
It produces a banding pattern similar to that of R-banding.它产生的显带模式与R显带相似。
NOR (silver) Staining.NOR（银染）染色。
This stain, of largely historic interest now, identified nucleolar organizing regions (NOR), which contain multiple copies of genes coding for rRNA, and which are sited on the satellite stalks of the acrocentric chromosomes.这种染色（如今主要具有历史意义）可识别核仁组织区（NOR），该区域包含多个编码rRNA的基因拷贝，位于近端着丝粒染色体的随体柄上。
Distamycin A/DAPI Staining.远霉素A/DAPI染色。
This fluorescent stain identifies the heterochromatin of chromosomes 1, 9, 15, 16, and Y.这种荧光染色可识别1、9、15、16号染色体及Y染色体的异染色质。
A particular use was to distinguish the inverted duplication 15 chromosome from other small marker chromosomes.其特殊用途是区分倒位重复15号染色体与其他小标记染色体。
Fluorescence In Situ Hybridization (FISH) and variations thereupon.荧光原位杂交（FISH）及其衍生技术。
The major cytogenetic advance of the 1990s was the ability to identify specific chromosomes, and parts of chromosomes, by in situ hybridization with labeled probes.20世纪90年代细胞遗传学的主要进展是通过标记探针的原位杂交识别特定染色体及其片段。
FISH has been widely used to detect submicroscopic deletions, and to characterize more obvious chromosome anomalies.FISH已广泛用于检测亚显微缺失及表征更明显的染色体异常。
A more focused use is in the assessment of the structural nature of imbalances revealed by microarray analysis (see below), with the probe from the genomic region targeted to the specific region identified by the array.更聚焦的应用在于评估微阵列分析（见下文）所揭示的结构性失衡，即用来自基因组区域的探针靶向阵列鉴定的特定区域。
Spectral Karyotyping (SKY).光谱核型分析（SKY）。
This is a variation upon the Multiplex-FISH theme.这是多重荧光原位杂交技术的一种变体。
Judicious combinations of fluorophores allow every chromosome to appear of a different color (Liehr et al. 2004).荧光染料的巧妙组合使得每条染色体呈现出不同的颜色（Liehr et al. 2004）。
The pictures resulting are certainly rather beautiful (Figures 1–1 and 2–2), and von Waldeyer-Hartz’s 1888 choice of the word “chromosome” becomes particularly apt.由此产生的图像确实相当美丽（图1–1和图2–2），而冯·瓦尔德耶-哈茨在1888年选择“染色体”一词也变得尤为贴切。
Targeted probes within segments of a chromosome enable some structural rearrangements to be very readily demonstrable (Figure 9–3).染色体片段内的靶向探针能够使某些结构重排非常容易地得到展示（图9–3）。
However, in fact it is more in the field of cancer cytogenetics that this methodology has been applied: a kaleidoscope of colors can rather clearly reveal the complexity of chromosomal changes accompanying tumor evolution.然而，实际上该方法更多地应用于癌症细胞遗传学领域：万花筒般的色彩能够相当清晰地揭示伴随肿瘤演变的染色体变化的复杂性。
Comparative Genomic Hybridization (CGH).比较基因组杂交（CGH）。
In CGH, differentially labeled, fluorophore-tagged DNA from the patient and a normal control (reference sample) is applied to a metaphase slide prepared from a “standard” normal person.在CGH中，来自患者和正常对照（参考样本）的差异标记、荧光染料标记的DNA被应用于从“标准”正常人制备的中期染色体玻片上。
Relative excesses and deficiencies of patient DNA bind competitively, with respect to the control, onto the reference chromosomes and yield different color intensities upon exciting the fluorophores.患者DNA的相对过量与不足，相对于对照，竞争性地结合到参考染色体上，并在激发荧光团时产生不同的颜色强度。
This procedure has been applied to archival pathology material. “High-resolution” CGH refers not to a more stretched chromosome preparation, but to a further level of sophistication of the computer software that is used to analyze the images, by adjusting for the idiosyncratic patterns that each homolog may have.这一程序已应用于存档的病理材料。“高分辨率”CGH并非指更拉伸的染色体制备，而是指用于分析图像的计算机软件通过调整每个同源染色体可能具有的特异性模式，达到了更高水平的精密程度。
Small imbalances may be identifiable by this approach, ~10 Mb or greater, and the nature of uncertain rearrangements clarified.通过这种方法可以识别出较小的不平衡，约10兆字节或更大，并且不确定重排的性质得以澄清。
Chromosomes examined by various techniques are illustrated in Figure 2–1.通过不同技术观察到的染色体如图2–1所示。
Full detail is to be found in Mark (2000), Miller and Therman (2001), Rooney (2023), Gersen and Keagle (2013), and Arsham et al. (2017), while Trask (2002) provides an historical span of the cytogeneticist’s skill.详见Mark（2000）、Miller与Therman（2001）、Rooney（2023）、Gersen与Keagle（2013）以及Arsham等人（2017）的论述，而Trask（2002）则从历史跨度上展现了细胞遗传学家的技艺。
CHROMOSOMAL MICROARRAY ANALYSIS Since the 2010s, chromosomal microarray (CMA) has become the first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies (Manning and Hudgins 2010; Miller et al. 2010).染色体微阵列分析自2010年代以来，染色体微阵列已成为发育障碍或先天性异常患者的一线临床诊断检测方法（Manning and Hudgins 2010；Miller et al. 2010）。
There are basically two microarray techniques: The first uses a CGH approach, much like that described above for Chromosome Analysis 21 chromosomal CGH; but this has gradually been replaced by the second, which uses single nucleotide polymorphisms (SNP) to assess the number of alleles in a sample.基本上有两种微阵列技术：第一种采用CGH方法，与上述用于染色体分析的21号染色体CGH非常相似；但这种方法已逐渐被第二种所取代，第二种利用单核苷酸多态性（SNP）来评估样本中的等位基因数量。
Although microarrays can differ in their genomic composition and substrates used for the analysis, most comprise thousands of spots of reference DNA sequences, applied in a precisely gridded manner upon a slide (or “chip”) in which the locations can be Figure 2–1.尽管微阵列在基因组组成和分析所用的底物上可能有所不同，但大多数包含数千个参考DNA序列的斑点，以精确网格化的方式应用于载玻片（或“芯片”）上，其位置可参见图2–1。
Chromosome pairs 1, 6, 15, 16, and Y and X stained by various techniques: plain stain (a), G-banding (b), replication banding (c), C-banding (d), Ag-NOR stain (e), and Q-banding (f). 22 BASIC CONCEPTS known by computer analysis.染色体对1、6、15、16以及Y和X染色体通过不同技术染色：普通染色（a）、G显带（b）、复制显带（c）、C显带（d）、Ag-NOR染色（e）和Q显带（f）。 22 通过计算机分析已知的基本概念。
Some commercial microarrays combine CGH and SNP detection on the same array.一些商业微阵列在同一阵列上结合了CGH和SNP检测。
Not that classical cytogenetics is likely to fade altogether from view: There are two crucial reasons for its continuing use in the laboratory.古典细胞遗传学不太可能完全从视野中消失：它在实验室中继续被使用有两个关键原因。
First, not all array results can give a definitive construction, and FISH is sometimes necessary to elucidate the cytogenetics.首先，并非所有阵列结果都能给出明确的构建，有时需要FISH来阐明细胞遗传学。
Second, the array cannot detect balanced rearrangements,1 and recognition of the carrier state will continue to need an old-fashioned chromosome test.第二，阵列无法检测到平衡重排¹，对携带者状态的识别仍需依赖传统的染色体检测。
And third, a rather subjective “reason” is that, by continuing to work with chromosomes, the molecular cytogeneticist/cytogenomicist will not lose the intuitive understanding of what chromosomes are really like, rather than seeing them merely as theoretical constructs or computer-screen displays.第三，一个较为主观的“理由”是，通过持续研究染色体，分子细胞遗传学家/细胞基因组学家不会丧失对染色体真实形态的直观理解，而非仅将其视为理论构造或计算机屏幕上的显示。
As mentioned above, the reporting of microarray results is a sophisticated exercise, and counselors need to be sophisticated readers of these reports.如上所述，微阵列结果的报告是一项复杂的任务，咨询师需要具备解读这些报告的高超能力。
Many laboratories now use depictions from one of the genome browsers— with a classic chromosome ideogram laying on its side at the top—to illustrate the precise extent of the imbalance, and noting the genes contained within this segment.许多实验室现在使用基因组浏览器中的图像——顶部横置的经典染色体模式图——来展示不平衡的精确范围，并标注该片段内包含的基因。
Comparative Genomic Hybridization The fundamental principle is essentially the same as in chromosomal CGH, noted above, but using the array, rather than the metaphase spread, as substrate.比较基因组杂交 基本原理与上述染色体CGH相同，但使用阵列而非中期染色体铺片作为底物。
Patient and Figure 2–2.患者与图2–2。
Spectral karyotyping.光谱核型分析。
Notes: Every chromosome is of a different color.注：每条染色体颜色不同。
Chromosome 4 stains light blue, and chromosome 8 is orange.4号染色体染为浅蓝色，8号染色体为橙色。
In this example, a child with Wolf-Hirschhorn syndrome (p. 392) manifests a distal 4p deletion with a very small segment from chromosome 8, the orange tip only just discernible (arrowed), in its place, from the karyotype 46,XY,der(4)t(4,8).在此例中，一名患有Wolf-Hirschhorn综合征（第392页）的儿童表现为远端4p缺失，并在该位置出现一段来自8号染色体的极小片段，仅可见橙色末端（箭头所示），核型为46,XY,der(4)t(4,8)。
Source: From T Ried et al., Chromosome painting: a useful art, Hum Mol Genet 7:1619–1626, 1998, with the permission of Oxford University Press. 1 Albeit that whole genome sequencing is being used to address this shortcoming (Ordulu et al. 2016; Redin et al. 2017).来源：摘自T Ried等，《染色体涂染：一项有用的技术》，Hum Mol Genet 7:1619–1626, 1998，经牛津大学出版社许可。¹ 尽管全基因组测序正被用于解决这一不足（Ordulu等，2016；Redin等，2017）。
11 CHROMOSOMAL MICROARRAY ANALYSIS
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Chromosome Analysis 23 control DNA are labeled in two different fluorophores, usually one that appears red and one that appears green.染色体分析 23 对照DNA用两种不同荧光染料标记，通常一种呈红色，一种呈绿色。
These labeled DNAs are applied to the microarray, and hybridization takes place.将这些标记的DNA应用于微阵列，进行杂交。
Typically, if the number of copies between the control and the patient are the same, the spot looks yellow (produced from an overlapping of equal amounts of red and green).通常，如果对照与患者的拷贝数相同，斑点呈黄色（由等量红色和绿色重叠产生）。
The fluorescent intensities of each dye are measured.测量每种染料的荧光强度。
If the patient has an excess at a locus (due to duplication or aneuploidy), the hybridization will more reflect the dye of the patient’s DNA.如果患者在某个位点存在过量（由于重复或非整倍体），杂交结果将更多反映患者DNA的染料颜色。
If the patient has a deficiency at a locus (loss due to deletion or unbalanced translocation), the hybridization will more reflect the dye of the control DNA (see the cover art of this book).如果患者在某个位点存在缺失（由于缺失或不平衡易位导致的丢失），杂交结果将更多反映对照DNA的染料颜色（参见本书封面图）。
Single Nucleotide Polymorphism (SNP) Array SNP arrays detect the number of alleles in a specimen (Figure 2–3) and provide two types of information.单核苷酸多态性（SNP）阵列 SNP阵列检测样本中的等位基因数量（图2–3），并提供两类信息。
First, the intensity of the signal arising from each SNP can be measured to produce a log2 ratio: A relative increase in signal intensity corresponds to copy number gain, and a decrease in signal intensity corresponds to deletion.首先，测量每个SNP产生的信号强度，计算log2比值：信号强度相对增加对应拷贝数增加，信号强度降低对应缺失。
Second, SNP arrays produce genotyping information: Heterozygosity, with two distinct alleles, can be distinguished from homozygosity, and from the presence of three alleles.其次，SNP芯片可产生基因分型信息：杂合性（具有两个不同等位基因）可与纯合性及三个等位基因的存在区分开来。
Apparent homozygosity may indicate a loss of DNA, such as a deletion, while three alleles may indicate a gain of DNA copy number, such as a duplication or trisomy.表观纯合性可能提示DNA缺失（如缺失），而三个等位基因则可能提示DNA拷贝数增加（如重复或三体）。
SNP-based microarrays have the added advantage of detecting uniparental disomy when the Figure 2–3.基于SNP的微阵列还具有检测单亲二体的额外优势，如图2–3所示。
SNP-based Microarray.基于SNP的微阵列。
Notes: Plot of chromosome 22 in a patient with a 22q11 deletion, using a SNP-based microarray that combines copy number (log2 ratio) and genotyping (B-allele frequency, blue dots) data.注释：使用结合拷贝数（log2比值）和基因分型（B等位基因频率，蓝点）数据的SNP微阵列，绘制一名22q11缺失患者的22号染色体图。
The copy number is reduced to a single copy in the region of the deletion, shown by the deviation of the log2 ratio (black dots) towards minus 1.在缺失区域，拷贝数减少至单拷贝，表现为log2比值（黑点）向负1偏移。
The genotyping plot (blue dots) demonstrates an absence of A/B heterozygous probes in the deleted region, showing only hemizygosity for the A or B alleles, thus also allowing inference of a deletion (indicated by pink shaded region).基因分型图（蓝点）显示缺失区域无A/B杂合探针，仅显示A或B等位基因的半合子状态，从而推断出缺失（以粉色阴影区域标示）。
Courtesy DI Francis.图片由DI Francis提供。
12 POLYMERASE CHAIN REACTION BASED APPLICATIONS
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24 BASIC CONCEPTS child’s results are compared to the parental genotypes.24 基本概念 将儿童的结果与父母基因型进行比较。
Isodisomy may be revealed, in the absence of parental samples, when the entire chromosome shows homozygosity, and chromosomal monosomy is an incompatible interpretation.在无父母样本的情况下，若整条染色体呈现纯合性，且染色体单体解释不成立，则可揭示同源二体。
POLYMERASE CHAIN REACTION-BASED APPLICATIONS A number of polymerase chain reaction (PCR) technologies can assess DNA copy number.基于聚合酶链反应的应用 多种聚合酶链反应（PCR）技术可评估DNA拷贝数。
These are targeted approaches to answer a specific question: How many copies of the target are present in the patient sample?这些是针对性方法，用于回答特定问题：患者样本中存在多少目标拷贝？
Multiplex ligation-dependent probe amplification (MLPA) uses pairs of probes to detect specific sections of the genome, identifying exon-level copy number variation across one or many genes.多重连接依赖性探针扩增（MLPA）使用成对探针检测基因组特定区域，识别一个或多个基因的外显子水平拷贝数变异。
Multiplexing of numerous exons allows detection in one reaction with high copy number accuracy.多重检测多个外显子可在一次反应中实现高拷贝数准确度的检测。
It can be combined with methylation-sensitive enzymes to detect the methylation status of a specific region.它可与甲基化敏感酶结合，检测特定区域的甲基化状态。
Quantitative real-time PCR (qPCR) combines amplification of a target DNA sequence with highly accurate quantification of the original template DNA target.定量实时PCR（qPCR）将目标DNA序列的扩增与原始模板DNA目标的高精度定量相结合。
Digital PCR (dPCR) partitions each PCR reaction strand to provide quantitation for a specific genomic location.数字PCR（dPCR）将每个PCR反应链分区，以对特定基因组位置进行定量。
Combined with oil droplet PCR (ddPCR) for partitioning of each PCR reaction, detection of variant fractions (in other words, mosaicism) as low as 1% is possible.结合油滴PCR（ddPCR）对每个PCR反应进行分区，可检测低至1%的变异分数（即嵌合体）。
Real-time Digital PCR (rdPCR) combines the above two methodologies, integrating the precision of dPCR with the real-time analysis capabilities of qPCR.实时数字PCR（rdPCR）结合上述两种方法，融合了dPCR的精度与qPCR的实时分析能力。
DNA SEQUENCING Short-Read Sequencing (Next Generation Sequencing) DNA methodologies based on massively parallel genomic sequencing of short strands of DNA (reads of up to a few hundred base pairs long) allow the entire expressed genetic complement, the “exome,” and even the whole genome to be tractable to interrogation.DNA测序 短读长测序（下一代测序）基于短DNA链（读长可达数百碱基对）的大规模并行基因组测序的DNA方法，使得整个表达的遗传互补序列（即“外显子组”），甚至全基因组，均可进行可操作的检测。
These methodologies were originally called “Next Generation Sequencing” (NGS) to distinguish from the traditional Sanger sequencing, but are more accurately referred to as short-read sequencing (SRS).这些方法最初被称为“下一代测序”（NGS），以区别于传统的桑格测序，但更准确地应称为短读长测序（SRS）。
In the cytogenetic field, SRS is routinely applied as a highly accurate molecular counting tool, sequencing cell-free DNA circulating in the maternal plasma, and mapping each sequence read back to its chromosome of origin.在细胞遗传学领域，SRS作为一种高度精确的分子计数工具被常规应用，用于对母体血浆中循环的无细胞DNA进行测序，并将每个序列读段映射回其来源染色体。
A similar technique is applied to aneuploidy detection in preimplantation embryos.类似的技术也应用于植入前胚胎的非整倍体检测。
At the time of writing, chromosome microarray remains the gold standard methodology for molecular karyotyping, but SRS is a promising alternative.在撰写本文时，染色体微阵列仍是分子核型分析的金标准方法，但SRS是一种有前景的替代方案。
Low-coverage genome sequencing can detect, with 100% sensitivity, copy number variants diagnosed by microarray, and the technology offers the additional benefit of detecting balanced chromosome rearrangements (Dong et al. 2014, 2016).低覆盖度基因组测序能以100%的灵敏度检测出微阵列诊断的拷贝数变异，并且该技术还具有检测平衡染色体重排的额外优势（Dong et al. 2014, 2016）。
Given that genome sequencing at higher levels of coverage offers considerable diagnostic yield for the diagnosis of sequence-level mutations, it is expected that, in time, a single SRS-based test will generate both copy number and sequence data, and will Chromosome Analysis 25 become the first-line test for the investigation of children with developmental disabilities and for prenatal diagnosis.鉴于更高覆盖度的基因组测序为序列水平突变的诊断提供了可观的诊断率，可以预期，未来基于SRS的单一检测将能同时生成拷贝数和序列数据，并将 染色体分析 25 成为发育障碍儿童检查和产前诊断的一线检测方法。
Long-Read Sequencing Long-read sequencing (LRS) analyzes DNA fragments of size tens to hundreds of kilobase pairs.长读长测序 长读长测序（LRS）分析大小为数十至数百千碱基对的DNA片段。
Currently, the two main technologies are PacBio’s (Pacific Biosciences) single-molecule real-time (SMRT) sequencing, and ONT’s (Oxford Nanopore Technologies) sequencing.目前，两种主要技术是PacBio（太平洋生物科学公司）的单分子实时测序（SMRT）和ONT（牛津纳米孔技术公司）的测序。
LRS can detect some structural variants that are missed by short-read sequencing, allowing these to be mapped with single base resolution, and is especially useful in resolving complex chromosome rearrangements.LRS可以检测一些短读长测序遗漏的结构变异，使其能够以单碱基分辨率进行定位，并且在解析复杂染色体重排方面特别有用。
LRS can also be used to phase variants, generate haplotypes, and to interrogate epigenetic modifications.LRS还可用于对变异进行定相、生成单倍型以及检测表观遗传修饰。
Optical Genome Mapping Optical Genome Mapping (OGM) can detect all classes of chromosome abnormalities encountered in the clinic, including aneuploidies, copy number variants from a few kilobases in size, and balanced structural rearrangements (Mantere et al. 2021; Xiao et al. 2024).光学基因组图谱 光学基因组图谱（OGM）可以检测临床中遇到的所有类型的染色体异常，包括非整倍体、大小从几千碱基起的拷贝数变异以及平衡结构重排（Mantere et al. 2021; Xiao et al. 2024）。
Linearized strands of high molecular weight DNA are labeled with fluorescent markers at specific sites, evenly spaced throughout the genome.高分子量DNA的线性化链在特定位点用荧光标记物标记，这些标记物均匀分布在整个基因组中。
The labeled DNA strands are then loaded into nanochannels, in which they are imaged using a fluorescence microscope, so that the order of markers for each strand can be mapped to the human genome reference.然后，标记的DNA链被加载到纳米通道中，在通道中通过荧光显微镜成像，从而可以将每条链上标记物的顺序映射到人类基因组参考序列上。
Methylation Detection Several of the techniques listed above can be applied to the detection of DNA methylation, following modification of the DNA sequence to distinguish between the unmethylated and methylated regions.甲基化检测 上述几种技术在对DNA序列进行修饰以区分未甲基化和甲基化区域后，可用于检测DNA甲基化。
Methylation strand modification is commonly performed by bisulfite conversion of the CpG sequence, or by methylation-sensitive enzyme digestion.甲基化链修饰通常通过CpG序列的亚硫酸氢盐转化或甲基化敏感酶切进行。
Direct detection of the methylated nucleotide can be achieved using nanopore-based LRS, whereby the methylated DNA strand passes through the nanopore at a slower rate than the unmethylated DNA strand.利用基于纳米孔的LRS可以实现对甲基化核苷酸的直接检测，其中甲基化的DNA链通过纳米孔的速度比未甲基化的DNA链慢。
Cytogenetic (or Cytogenomic) Reports Chromosomal findings from molecular analyses are often presented in an intuitive pictorial form, such as, for example, the display in Figure 2–3.细胞遗传学（或细胞基因组学）报告 来自分子分析的染色体发现通常以直观的图形形式呈现，例如图2-3中的显示。
Although cytogenetics will continue to evolve, whatever techniques come to be used, the fundamental purpose of the cytogenetic report will of course remain the same.尽管细胞遗传学将继续发展，无论采用何种技术，细胞遗传学报告的基本目的当然将保持不变。
Descriptions about the technologies used will be important addenda to reports, because they may inform the clinician about the interpretation of the chromosome analysis and the possible need for further analysis.关于所用技术的描述将是报告的重要补充，因为它们可以告知临床医生关于染色体分析的解释以及可能需要进行进一步分析的情况。
Reports may also include a listing of presumed significant genes in the region, a comment upon imprinting, and the likelihood of benign报告还可能包括区域内推定重要基因的列表、关于印记的评论以及良性可能性。
13 GENETIC COUNSELING CONSIDERATIONS
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26 BASIC CONCEPTS versus causative genomic changes.26 基本概念 versus 因果性基因组变化。
A pedantic but important point is that the genome “build” be noted.一个迂腐但重要的观点是，基因组“构建”应被注意。
GENETIC COUNSELING CONSIDERATIONS Mostly, the abnormalities found by molecular technologies have clear clinical relevance for the patient and the family.遗传咨询考量 大多数情况下，分子技术发现的异常对患者及其家庭具有明确的临床相关性。
However, higher resolution strategies may uncover DNA changes of unclear clinical significance (as we discuss at length in Chapter 18).然而，更高分辨率的策略可能发现临床意义不明确的DNA变化（我们将在第18章详细讨论）。
Such findings may lead to testing of additional family members, parents, grandparents, and sometimes siblings, to understand the relationship, if any, between the DNA alteration and the clinical phenotype or medical condition of the patient.此类发现可能导致对更多家庭成员、父母、祖父母，有时是兄弟姐妹进行检测，以了解DNA改变与患者临床表型或医学状况之间是否存在关联。
The possibility of findings of unclear clinical significance should be discussed when ordering the test, especially in the prenatal setting.在订购检测时，尤其是在产前环境中，应讨论发现临床意义不明确结果的可能性。
Because these molecular-based tests have the ability to interrogate the entire genome, the pretest genetic counseling should include information about uncovering unwanted information, such as loci that could predispose to cancer, or to adult-onset disorders.由于这些基于分子的检测能够探查整个基因组，检测前遗传咨询应包括关于发现不必要信息的内容，例如可能易患癌症或成人发病疾病的位点。
The use of SNP arrays may uncover substantial stretches of homozygosity due to consanguineous or even incestuous relationships (Schaaf et al. 2011).SNP阵列的使用可能揭示因近亲甚至乱伦关系导致的大段纯合性（Schaaf等人，2011年）。
These counseling caveats notwithstanding, the higher resolution potential of these new technologies will increase the detection rate of chromosome abnormalities, and will much improve our ability to make diagnoses, and to provide the answers that families seek.尽管存在这些咨询注意事项，这些新技术的更高分辨率潜力将提高染色体异常的检出率，并大大改善我们做出诊断以及提供家庭所寻求答案的能力。
The counselor need not be expert in the nature of the technologies outlined above, but should have a broad understanding of the different applications and of what each can, or cannot, offer in the clinical setting.咨询师无需精通上述技术的本质，但应广泛了解不同应用及其在临床环境中能或不能提供什么。

3 Chapter 3

14 MEIOSIS
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28 BASIC CONCEPTS Chapter 14) or to a deletion of a gene (e.g., Pitt-Hopkins syndrome, Chapter 14), and thus diagnosable on cytogenomic technology.28 基本概念 第14章）或基因缺失（例如，Pitt-Hopkins综合征，第14章），因此可通过细胞基因组技术诊断。
The analysis of copy number variants (CNVs)—short segments of genomic material in excess or deficiency—is generally regarded as a chromosomal exercise.拷贝数变异（CNVs）——基因组物质中过量或不足的短片段——的分析通常被视为染色体层面的工作。
We will largely confine ourselves (Chapter 18) to those CNVs which are known to be pathogenic; but there is also blurring, here, in terms of CNVs, whose harmlessness (or not) is uncertain.我们将在很大程度上（第18章）局限于已知致病的CNVs；但在此处，关于CNVs的无害性（或非无害性）也存在模糊之处。
We focus first upon the classic chromosomal disorders.我们首先聚焦于经典染色体疾病。
Most of these arise at meiosis.这些大多发生在减数分裂期间。
A gamete from a 46,N person may acquire an extra (but normal) chromosome, and this would lead to a full aneuploidy in a conceptus of theirs: a trisomy.来自46,N个体的配子可能获得一条额外（但正常）的染色体，这将导致其受精卵出现完全非整倍体：三体性。
Or, partial aneuploidy may be due to meiotic malsegregation having taken place in gametogenesis of a 46,rea (rea = rearrangement) parent carrying a balanced rearrangement.或者，部分非整倍体可能由于携带平衡重排的46,rea（rea = 重排）父母在配子发生过程中发生减数分裂错误分离所致。
De novo (“of new”; that is, with normal parental karyotypes) partial aneuploidies may have been generated at a meiotic division, or at a premeiotic germ cell mitosis; where there is normal/aneuploid mosaicism, a postmeiotic event in the embryo is implicated.新生（“新的”；即父母核型正常）部分非整倍体可能产生于减数分裂分裂或减数分裂前生殖细胞有丝分裂；若存在正常/非整倍体嵌合体，则涉及胚胎中的减数分裂后事件。
While it may not be possible to presume with reasonable confidence where the original error lay, a theoretical consideration of the point at which a chromosomal defect arose—before, during, or after meiosis—can underpin a useful understanding.虽然可能无法合理确信地推断原始错误所在，但对染色体缺陷产生时间点（减数分裂前、期间或之后）的理论考量可支撑有用的理解。
It thus behooves us to appreciate the broad processes of meiotic and mitotic cell divisions.因此，我们有责任理解减数分裂和有丝分裂细胞分裂的广泛过程。
MEIOSIS Meiosis in Chromosomally Normal Persons The purpose of meiosis is to achieve the reduction from the diploid state of the primary gametocyte (2n = 46) to the haploid complement of the normal gamete (n = 23); and to ensure genetic variation in the gametes.减数分裂 染色体正常个体的减数分裂 减数分裂的目的是实现从初级配子母细胞的二倍体状态（2n=46）减少到正常配子的单倍体染色体组（n=23）；并确保配子中的遗传变异。
The latter requirement is met by enabling the independent assortment of homologs (the physical basis of Mendel’s second law)2 and by providing a setting for recombination between homologs.后者通过实现同源染色体的独立分配（孟德尔第二定律的物理基础）²，并为同源染色体之间的重组提供条件而得以满足。
While we do not dwell on recombination per se, this is, to the classical geneticist, a raison d’être of the chromosome: “From the long perspective of evolution, a chromosome is a bird of passage, a temporary association of particular alleles” (Lewin 1994).虽然我们不专门讨论重组本身，但对经典遗传学家而言，这却是染色体存在的理由：“从进化的长远视角来看，染色体是一只过路鸟，是特定等位基因的临时组合”（Lewin 1994）。
The mature gamete is produced after the two meiotic cell divisions: meiosis I and meiosis II, the cells going through stages of oögonium/spermatogonium → primary gametocyte → secondary gametocyte → mature gamete (or polar body).成熟的配子是在两次减数分裂（减数第一次分裂和减数第二次分裂）后产生的，细胞依次经历卵原细胞/精原细胞→初级配子母细胞→次级配子母细胞→成熟配子（或极体）的阶段。
As per the classical description (Figure 3–1), the chromosomes of the (diploid) primary gametocyte entering meiosis I do not divide at the centromere, and they remain, following cell division into secondary gametocytes, as double-chromatid chromosomes.按照经典描述（图3–1），进入减数第一次分裂的（二倍体）初级配子母细胞的染色体不在着丝粒处分裂，并且在分裂为次级配子母细胞后，它们仍保持为双染色单体的染色体。
With only one of each homolog, the cell is in the haploid state.每个同源染色体只有一个拷贝时，细胞处于单倍体状态。
In meiosis II, the chromosomes of the secondary gametocytes separate into their component single chromatids, and this cell division gives rise to the (haploid) gametes.在减数分裂II中，次级配子母细胞的染色体分离为组成它们的单个染色单体，此次细胞分裂产生（单倍体）配子。
In the male, the cells produced from one primary gametocyte are the four spermatids, which mature into spermatozoa.在男性中，由一个初级配子母细胞产生的细胞是四个精细胞，它们成熟为精子。
In the female, the cells are the mature ovum and its polar bodies. (In fact, 2 The law of independent assortment: During gamete formation, the segregation of the alleles of one allelic pair is independent of the segregation of the alleles of another allelic pair.在女性中，这些细胞是成熟的卵细胞及其极体。
The exception: If two loci are close together—“linked”—on the same chromosome.如果两个基因座在同一条染色体上相距很近——“连锁”。
Origins and Consequences of Chromosome Pathology 29 Figure 3–1.染色体病理学的起源与后果 29 图3–1
Meiosis I.减数分裂 I。
Chromosomal behavior during meiosis I, according to the classical model.减数分裂I期间的染色体行为，依据经典模型。
Circles represent germ cells: at (a) oögonia and spermatogonia (gonocytes); at (b–d) primary oöcytes and spermatocytes (gametocytes); and at (e) secondary oöcytes and spermatocytes.圆圈代表生殖细胞：(a) 卵原细胞和精原细胞（生殖母细胞）；(b–d) 初级卵母细胞和初级精母细胞（配子母细胞）；(e) 次级卵母细胞和次级精母细胞。
One crossover has occurred between the long arms of one chromatid of each homolog.两条同源染色体中各一条染色单体的长臂之间发生了一次交换。
Following meiosis I, the chromosome number has halved (reduction division).减数第一次分裂后，染色体数目减半（减数分裂）。
In oögenesis, one of the two cells at (d) would be the first polar body, and would typically not enter meiosis II. 30 BASIC CONCEPTS it is not until sperm penetration that meiosis II in the ovum is completed.) Figure 3-2 shows the appearances of the chromosomes at these different stages of meiosis.在卵子发生过程中，(d)处的两个细胞之一将成为第一极体，并且通常不会进入减数第二次分裂。 30 基本概念 直到精子穿入，卵母细胞中的减数第二次分裂才完成。）图3-2显示了减数分裂这些不同阶段染色体的形态。
Each gamete thus contains a haploid set of chromosomes.因此，每个配子都包含一套单倍体染色体。
The diploid complement is restored at conception, with the union of two haploid gametes.二倍体互补在受精时恢复，通过两个单倍体配子的结合。
The moment of conception, as the embryologist sees it, is not at sperm penetration but only when the two pronuclei have fused to form a single nucleus (“syngamy”).胚胎学家认为，受孕的时刻并非精子穿透之时，而是两个原核融合形成单个细胞核（“合子核”）之际。
Note that spermatogenesis divides the cytoplasm evenly, so that after meiosis II there are four gametes of equal size.精子发生过程中细胞质均匀分裂，因此在减数第二次分裂后会产生四个大小相等的配子。
The sperm head that penetrates the ovum comprises almost entirely nuclear material; the tail is cast off.穿透卵子的精子头部几乎完全由核物质构成；尾部则被丢弃。
In oöcytes, cytoplasmic division is markedly uneven, producing a secondary oöcyte and first polar body after meiosis I, and the mature ovum and second polar body at meiosis II.3 The ovum and the polar bodies each have a haploid chromosome set, but the ovum retains almost all of the cytoplasm.4 Another major sex difference concerns the timing of gamete maturation.在卵母细胞中，胞质分裂明显不均等，减数第一次分裂后产生一个次级卵母细胞和第一极体，减数第二次分裂时形成成熟卵子和第二极体。³ 卵子和极体各有一套单倍体染色体，但卵子保留了几乎全部细胞质。⁴ 另一个重要的性别差异涉及配子成熟的时间。
In the female, meiosis is partway through, in the late prophase of meiosis I, by the eighth month of intrauterine life (the actual process of recombination taking place during weeks 16–19 of fetal life).在女性中，减数分裂进行到一半，处于减数分裂I的晚期前期，此时为宫内生命的第八个月（实际的重组过程发生在胎儿生命的第16至19周）。
At birth, a female baby has around a third of a million oöcytes (Figure 20–30).出生时，女婴约有三十万个卵母细胞（图20–30）。
Most of this pool is gradually lost, but those eggs destined to mature stay in a “frame-freeze” until they enter ovulation some one to five decades thereafter,5 and meiosis recommences.这个池中的大部分卵母细胞逐渐流失，但那些注定要成熟的卵母细胞会保持“定格”状态，直到此后一至五十年进入排卵期，减数分裂才重新开始。
Testicular stem cells (spermatogonia), on the other hand, Figure 3–2.另一方面，睾丸干细胞（精原细胞），如图3–2所示。
The Chromosomes in Human Gametes.人类配子中的染色体。
Notes: The karyotype from a 23,X egg (left), showing the haploid set of double-chromatid chromosomes following the completion of the reduction division of meiosis I (cf.23,X卵子的核型（左），显示减数第一次分裂完成后的单倍体双染色单体染色体组（参见）。
Figure 3–1d).图3–1d)
The chromosome spread (center) from a 46.XY spermatocyte, the homologs having come together as bivalents in mid-meiosis I (cf.染色体铺展（中央）来自一个46，XY的精母细胞，同源染色体在减数第一次分裂中期已配对形成二价体（参见
Figure 3–1b,c).图3–1b,c)
The autosomal bivalents have their homologous segments aligned, whereas the X-Y bivalent aligns only at the tips of Xp and Yp.常染色体二价体具有同源片段对齐，而X-Y二价体仅在Xp和Yp的末端对齐。
The single-chromatid chromosomes of a 23,Y sperm (right) at meiosis II (cf.23,Y精子的单染色单体染色体（右）在减数分裂II期（参见
Figure 3–1e).图3–1e)
Sources: From O Samura et al., Sperm and oocyte chromosomal abnormalities, Biomolecules 13:1010, 2023; and L Uroz and C Templado, Meiotic non-disjunction mechanisms in human fertile males, Hum Reprod 27:1518–1524, 2012.来自 O Samura 等人，《精子与卵母细胞染色体异常》，《生物分子》13:1010，2023年；以及 L Uroz 和 C Templado，《人类可育男性减数分裂不分离机制》，《人类生殖》27:1518–1524，2012年。
Courtesy O Samura, and with the permission of MDPI; and courtesy L Uroz and C Templado, and with the permission of the European Society of Human Reproduction and Embryology and Oxford University Press. 3 The first polar body does not normally undergo (a biologically pointless) meiosis II. 4 Cytoplasm contains the mitochondria, and transmission of mitochondrial DNA is maternal.承蒙O Samura惠允，并获MDPI许可；承蒙L Uroz与C Templado惠允，并获欧洲人类生殖与胚胎学学会及牛津大学出版社许可。
The mitochondrial genome has been described, somewhat whimsically, as chromosome 25, or the M chromosome.线粒体基因组曾被有些戏谑地称为第25号染色体，或M染色体。
In not otherwise referring to this “chromosome” we are not seeking to deny its importance or interest! 5 As Eichenlaub-Ritter (2012) points out, oöcytes are one of the longest-lived cells in the body.若不提及此“染色体”，我们并非意在否认其重要性或趣味性！
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Origins and Consequences of Chromosome Pathology 31 do not begin to enter meiosis until the onset of puberty.染色体病理学的起源与后果 31 直到青春期开始才进入减数分裂。
Thereafter, millions of mature sperm are continuously produced.此后，数百万个成熟的精子被持续不断地产生。
Meiosis in Detail.减数分裂详解。
We now examine more closely the details of meiosis, according to the classical model.现在我们更仔细地检查减数分裂的细节，依据经典模型。
During the final mitotic division in the primary gametocyte, the homologous pairs of chromosomes have (as with any mitosis) replicated their DNA to change from the single-chromatid to the double-chromatid stage.在初级配子母细胞的最后一次有丝分裂中，同源染色体对（如同任何有丝分裂一样）已复制其DNA，从单染色单体阶段转变为双染色单体阶段。
They now enter into the meiotic cell cycle (Figure 3–1a).它们现在进入减数分裂细胞周期（图3–1a）。
As meiosis I proceeds to prophase, chromosomes conduct a “homology search” and come together and pair, with matching loci alongside each other (Figure 3–1b).随着减数分裂I进入前期，染色体进行“同源搜索”并相互靠近配对，使匹配的基因座并排排列（图3–1b）。
This process—synapsis—continues with a more intimate pairing of the homologs, starting at the tips of the chromosomes and proceeding centrally, and the synaptonemal complex is formed (Barlow and Hultén, 1996).这一过程——联会——随着同源染色体从染色体末端开始向中央更紧密地配对而继续进行，并形成联会复合体（Barlow and Hultén, 1996）。
The paired chromosomes themselves are called bivalents.6 Synapsis sets the stage for an exchange of matching chromosome segments; this is the process of recombination, or crossing-over (Figure 3–1c).配对染色体本身被称为二价体。6 联会为匹配染色体片段的交换奠定基础；这一过程即为重组，或称交叉互换（图3–1c）。
Next, desynapsis occurs (the diplotene stage), with dissociation of the synaptonemal complex and the formation of chiasmata.接着，发生联会解除（双线期），伴随联会复合体的解离和交叉的形成。
Now, the two homologous chromosomes disjoin and go to opposite poles of the cell.现在，两条同源染色体分离，移向细胞的两极。
This is the anaphase stage; the orderly movement of chromosomes during this sequence is facilitated if synapsis, recombination, and chiasmata formation have proceeded normally.这是后期阶段；如果联会、重组和交叉形成过程正常进行，则有助于此过程中染色体的有序移动。
Finally, the cell divides into the two daughter cells (Figure 3–1d).最后，细胞分裂成两个子细胞（图3–1d）。
How the chromosomes are distributed—which chromosome goes to which pole—is called segregation.染色体的分布方式——哪条染色体前往哪一极——被称为分离。
Normally, each daughter cell gets one of each of the pair of chromosomes, and this is referred to as one-to-one (1:1) segregation.通常，每个子细胞会得到每对染色体中的一条，这被称为一对一（1:1）分离。
Uniquely in the meiosis I cell division daughter cells are produced with double-chromatid chromosomes.在减数第一次分裂中，子细胞独特地产生具有双染色单体的染色体。
These gametocytes then enter meiosis II (with the exception of the first polar body).这些配子母细胞随后进入减数第二次分裂（第一极体除外）。
In this cycle, the chromosomes do not replicate because they are already in the double-chromatid state.在此周期中，染色体不再复制，因为它们已处于双染色单体状态。
The chromosomes separate at the centromere, and the resulting single-chromatid chromosomes disjoin, one going to each pole, resembling a mitotic division (Figure 3–1e).染色体在着丝粒处分离，产生的单染色单体染色体分开，各移向一极，类似于有丝分裂（图3–1e）。
The foregoing, classical construction held sway since practically the beginning of human cytogenetics, and it remains very useful conceptually; but its primacy has since been challenged.上述经典理论自人类细胞遗传学诞生之初便占据主导地位，且在概念上仍非常有用；但其首要地位后来受到了挑战。
One alternative description puts the events of meiosis I and II in the reverse order: That is, the chromosomes separate into chromatids at meiosis I and then segregate into daughter cells at meiosis II (Figure 3–3).另一种描述将减数分裂I和II的事件顺序颠倒：即染色体在减数分裂I时分离为染色单体，然后在减数分裂II时分配到子细胞中（图3–3）。
This has been called reverse segregation (Ottolini et al. 2015; Webster and Schuh 2017).这被称为反向分离（Ottolini等，2015；Webster和Schuh，2017）。
The other, very important, retelling of the events of meiosis is premature separation of sister chromatids (PSSC).另一种非常重要的减数分裂事件重述是姐妹染色单体过早分离（PSSC）。
This is, in fact, the predominant mechanism in the female, and is important in the male (Ottolini et al. 2015; Sakakibara et al. 2015).事实上，这是女性中的主要机制，在男性中也具有重要意义（Ottolini等，2015；Sakakibara等，2015）。
It refers to the “precocious” separation of chromatids during meiosis I, as initially proposed by Angell (1997), and involves three sequential events (Figure 3–4).它指的是减数分裂I期间染色单体的“早熟”分离，最初由Angell（1997）提出，涉及三个连续事件（图3–4）。
First, the (double-chromatid) homologs fail to pair during meiosis I; or, if they do pair, they separate again before meiosis I is complete.首先，（双染色单体的）同源染色体在减数分裂I期间未能配对；或者，即使配对，也在减数分裂I完成前再次分离。
In other words, instead of the two (double-chromatid) chromosomes existing as a conjoined bivalent, they exist as two separate univalents.换言之，两个（双染色单体的）染色体并非以联合二价体的形式存在，而是以两个独立的单价体存在。
Second, these univalents are prone to “predivide”—that is, the separation of the two chromatids that should (on the classical plan) happen 6 Since, at the level of the chromatid, the bivalent pair contains four elements, the word tetrad can also be used in this setting; in this sense, the cell at this stage of the cycle has 23 × 4 = 92 chromatids. 32 BASIC CONCEPTS Figure 3–3.其次，这些单价体容易发生“预分裂”——即本应在减数分裂II发生的两个染色单体分离，反而在第一次减数分裂周期中发生。
Reverse Segregation.由于在染色单体水平上，二价体对包含四个元素，因此也可使用“四分体”一词；在此意义上，该周期阶段的细胞具有23 × 4 = 92条染色单体。
Chromosomal behavior during meiosis, specifically ovarian meiosis, according to the model of “reverse segregation.” Circles represent germ cells: at (a) oögonia; at (b–d) primary oöcyte; at (d) first polar body (PB1); and at (e) secondary oöcyte and the second polar body (PB2).反向分离。
One crossover has occurred between the long arms of one chromatid of each homolog.根据“反向分离”模型，减数分裂期间（特别是卵巢减数分裂）的染色体行为。圆圈代表生殖细胞：（a）卵原细胞；（b–d）初级卵母细胞；（d）第一极体（PB1）；（e）次级卵母细胞和第二极体（PB2）。
The single-chromatid chromosomes separate at (d); this is the step that defines “reverse segregation.” Meiosis II follows at (e).在每个同源染色体的一条染色单体的长臂之间发生了一次交换。
Note that the pairs of cells after meiosis II (ovum + second polar body) have homologs of opposite parental origin (non-sister chromatids).单染色单体染色体在（d）处分离；这是定义“反向分离”的步骤。减数分裂II随后在（e）处进行。
In the classical model (Figure 3–1), the homologs in these pairs would always be of the same parental origin (sister chromatids).注意减数分裂II后的细胞对（卵细胞+第二极体）具有相反亲本来源的同源染色体（非姐妹染色单体）。
It was this distinction which, along with other evidence, pointed Ottolini et al. (2015) toward proposing this new model.在经典模型中（图3–1），这些细胞对中的同源染色体总是具有相同亲本来源（姐妹染色单体）。
Origins and Consequences of Chromosome Pathology 33 at meiosis II, instead takes place while they are still in the first meiotic cycle.正是这一区别，连同其他证据，促使Ottolini等人（2015）提出了这一新模型。
This could happen to both univalents or just the one, and these would then exist as single-chromatid chromosomes.这可能发生在两个单价体或仅一个单价体上，随后它们将以单染色单体染色体的形式存在。
The oöcyte in Figure 3–6 (lower) may be an example of asymmetric segregation due to this process, having received a double-chromatid and a single-chromatid chromosome 21.图3–6（下方）中的卵母细胞可能是由于该过程导致的不对称分离的一个例子，它接收了一条双染色单体和一条单染色单体的21号染色体。
Third, at anaphase of meiosis I, these double- or single-chromatid chromosomes segregate independently to the oöcyte and polar body, or mature spermatocytes.第三，在减数分裂I的后期，这些双染色单体或单染色单体染色体独立分离到卵母细胞和极体，或成熟精母细胞。
Chromosomal pathology arises when these processes of disjunction and segregation go wrong—malsegregation and nondisjunction.当这些分离和分配过程出现错误时——即错误分离和不分离——就会产生染色体病理。
Figure 3–4.图3–4。
Premature Separation of Sister Chromatids.姐妹染色单体的过早分离。
Nondisjunction following “predivision” of one homolog into its component chromatids in meiosis I (Angell’s hypothesis).在减数分裂I中，一个同源染色体“预分裂”为其组成染色单体后的不分离（安吉尔假说）。
The asterisked gamete reflects the complement of the oöcyte in Figure 3–6 (lower).带星号的配子反映了图3–6（下方）中卵母细胞的染色体组成。
In öogenesis, one of the two cells following meiosis I would be the first polar body, which might or might not proceed to meiosis II.在卵子发生中，减数分裂I后的两个细胞之一将成为第一极体，它可能进入也可能不进入减数分裂II。
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34 BASIC CONCEPTS Malsegregation and Nondisjunction in Meiosis Malsegregation (or missegregation) is remarkably frequent at meiosis, and in consequence many human conceptions are trisomic or monosomic.34 基本概念 减数分裂中的错误分离与不分离 错误分离（或错分离）在减数分裂中极为常见，因此许多人类受孕胚胎表现为三体或单体。
Malsegregation is a “catch-all” term; in principle, nondisjunction specifically refers to the failure of homologous chromosomes to segregate symmetrically at cell division, although in practice it is often considered (and we sometimes do) as “the inclusion of both daughter chromosomes in the same nucleus, by whatever mechanism” (Miller and Therman 2001).错误分离是一个“包罗万象”的术语；原则上，不分离特指同源染色体在细胞分裂时未能对称分离，尽管在实践中它常被视为（我们有时也如此）“通过任何机制将两个子染色体纳入同一细胞核”（Miller and Therman 2001）。
The process of malsegregation is described according to two models: the classical description of nondisjunction (Figure 3–5), and a modern description based upon the PSSC model as described above.错误分离的过程根据两种模型描述：经典的不分离描述（图3–5），以及基于上述PSSC模型的现代描述。
While the classical model has long been seen as the typical process, in fact, as Gabriel et al. (2011) write, “it appears to be a relatively minor player” and “the received wisdom that non-disjunction [sensu stricto] is the primary mechanism leading to human aneuploidy should be reconsidered.” Nevertheless, and taking a conservative viewpoint,7 we first set out in detail the model that has appeared in textbooks for generations, but then pay due attention to the more recent knowledge.尽管经典模型长期以来被视为典型过程，但事实上，正如Gabriel等人（2011）所写，“它似乎只是一个相对次要的角色”，并且“认为不分离[狭义]是导致人类非整倍体的主要机制这一传统观点应重新考虑。”然而，采取保守观点后，我们首先详细阐述已在教科书中出现数代的模型，但随后对更新的知识给予适当关注。
The classical description of the mechanism of meiotic nondisjunction is as follows: In a chromosomally normal person, if the pair of homologs comprising a bivalent at meiosis I fail to separate (fail to disjoin8), one daughter cell will have two of the chromosomes, and the other will have none.减数分裂不分离机制的经典描述如下：在染色体正常的人中，如果减数分裂I中构成二价体的一对同源染色体未能分离（未能分开），则一个子细胞将拥有两条染色体，而另一个子细胞将一条也没有。
This is 2:0 segregation (Figures 3–5 and 3–6, upper).这就是2:0分离（图3–5和图3–6，上方）。
In other words, one gametocyte is disomic for that homolog, and the other is nullisomic.换句话说，一个配子母细胞对该同源染色体是二体的，而另一个是零体的。
Or, nondisjunction may occur in meiosis II, meiosis I having proceeded normally.或者，不分离可能发生在减数分裂II中，而减数分裂I正常进行。
In meiosis II, it is the chromatids that fail to separate (Figure 3–5b).在减数分裂II中，是染色单体未能分离（图3–5b）。
Following these nondisjunctional errors, the conceptus, at fertilization, ends up trisomic or monosomic, assuming the other gamete to be normal (Figure 3–7a, b).在这些不分离错误之后，受精时的受孕胚胎最终成为三体或单体，假设另一个配子正常（图3–7a, b）。
Trisomy or monosomy in the offspring of normal parents is called primary trisomy or primary monosomy.正常父母后代中的三体或单体称为原发性三体或原发性单体。
Concerning meiotic malsegregation following the alternative premature separation of sister chromatids scenario Figure 3–4 sets out the picture.关于姐妹染色单体提前分离情景下的减数分裂错误分离，图3–4展示了这一图像。
As the oögonium and spermatogonium enter meiosis, one double-chromatid homolog “pre-divides” and now consists of a pair of single-chromatid chromosomes.当卵原细胞和精原细胞进入减数分裂时，一条双染色单体的同源染色体“提前分裂”，现在由一对单染色单体的染色体组成。
If these chromosomes were then to segregate symmetrically, at meiosis I, the primary gametocytes resulting would have a balanced constitution; but if it is asymmetric—as in the example in Figure 3–4—one gametocyte has an extra chromatid, while the other has only one.如果这些染色体随后在减数分裂I中对称分离，产生的初级配子细胞将具有平衡的组成；但如果分离是不对称的——如图3-4中的例子——一个配子细胞会多出一条染色单体，而另一个则只有一条。
As meiosis II proceeds, giving rise to the secondary gametocytes, it transpires that two are normal haploid, one is diploid, and one “nulliploid.” The oöcyte in Figure 3–6 (lower) may be an example of asymmetric segregation due to this process, having received a double-chromatid and a single-chromatid chromosome 21.9 Polar body and embryo studies in the IVF laboratory suggest that, at least at an older maternal age, half of all aneuploidy in the oöcyte results from meiosis I,10 about a third from meiosis II and a small fraction from meiosis I nondisjunction (Verdyck et al. 2023). 7 “Be not the first by whom the new are tried, Nor yet the last to lay the old aside.” Alexander Pope, An Essay on Criticism, 1711. 8 Note that disjunction is a normal process, and nondisjunction is not; there is no such word as dysjunction. 9 Certain terminologies and nomenclature may be mentioned here.随着减数第二次分裂的进行，产生次级配子母细胞，结果发现两个是正常单倍体，一个是二倍体，一个是“零倍体”。图3–6（下方）中的卵母细胞可能是由于这一过程导致的不对称分离的一个例子，它接收了一条双染色单体和一个单染色单体的21号染色体。9 在体外受精实验室中对极体和胚胎的研究表明，至少在母亲年龄较大时，卵母细胞中所有非整倍体的一半源于减数第一次分裂，10 约三分之一源于减数第二次分裂，一小部分源于减数第一次分裂的不分离（Verdyck et al. 2023）。7 “不要成为第一个尝试新事物的人，也不要成为最后一个抛弃旧事物的人。”——亚历山大·蒲柏，《论批评》，1711年。8 注意，分离是正常过程，而不分离则不是；不存在“dysjunction”这样的词。9 此处可能提及某些术语和命名法。
A gamete with an extra chromosome is hyperhaploid, with a karyotype written as, for example, 24,X,+21.具有额外染色体的配子为超单倍体，其核型可写为例如24,X,+21。
A gamete missing a chromosome is hypohaploid (e.g., 22,Y,–21).缺少一条染色体的配子是亚单倍体（例如22,Y,–21）。
If, at meiosis I, the extra chromosome is present only as a single chromatid (e.g., the asterisked oöcyte in Figure 3–4), the abbreviation cht (for chromatid) is used: thus, 24,X,+21cht.如果在减数分裂I中，额外的染色体仅以单条染色单体形式存在（例如图3-4中带星号的卵母细胞），则使用缩写cht（代表染色单体）：即24,X,+21cht。
The ISCN (2024) provides nomenclature for meiotic cells, and an extra 21 at meiosis I, present as a univalent, would be denoted as MI,24,+I(21). 10 This category may also have included examples of reverse segregation.ISCN（2024）提供了减数分裂细胞的命名规则，在减数第一次分裂中额外出现一个21号染色体，以单价体形式存在，可记为MI,24,+I(21)。
Origins and Consequences of Chromosome Pathology 35 Figure 3–5.染色体病理学的起源与后果 35 图3–5。
The classical view of the mechanics of nondisjunction.不分离机制的经典观点。
The asterisked gamete reflects the complement of the oöcyte in Fig. 3–6 (upper), with respect to one of the G-group chromosomes.带星号的配子反映了图3-6（上）中卵母细胞在G组染色体之一上的互补情况。
In oögenesis, one of the two cells following meiosis I would be the first polar body, which typically does not proceed to meiosis II.在卵子发生过程中，减数第一次分裂后的两个细胞之一将成为第一极体，它通常不会进入减数第二次分裂。
A process somewhat intermediate between these two major mechanisms is achiasmate nondisjunction, in which the homologs had never joined and then segregate together to the same daughter cell.介于这两种主要机制之间的某种过程是缺刻不分离，其中同源染色体从未配对，然后一起分离到同一个子细胞中。
The end result is the same as if classical nondisjunction had occurred, but without any recombination (Uroz and Templado 2012). 36 BASIC CONCEPTS Figure 3–8 summarizes these several scenarios, with particular reference to the more vulnerable gamete, which is to say, the egg.最终结果与经典的不分离现象相同，但没有任何重组（Uroz和Templado 2012）。 36 基本概念 图3–8总结了这几种情况，特别关注了更脆弱的配子，即卵细胞。
Frequencies of Meiotic Malsegregation The very considerable majority of human aneuploidy due to meiotic malsegregation, takes place during oögenesis.减数分裂错误分离的发生频率 人类非整倍体绝大多数由减数分裂错误分离引起，且主要发生在卵子发生过程中。
Remarkably high fractions of mature oöcytes are Figure 3–6.图3–6中，成熟卵母细胞的比例异常高。
Oöcyte chromosomes at metaphase of meiosis II, showing nondisjunction of a G-group chromosome having occurred at the preceding first meiotic division.减数第二次分裂中期的卵母细胞染色体，显示在之前的第一次减数分裂中发生了G组染色体不分离。
Upper, oöcyte with classical nondisjunctional disomy, showing an additional G-group double-chromatid chromosome.上方，具有经典不分离二体的卵母细胞，显示一条额外的G组双染色单体染色体。
Possibly the arrowed pair are chromosome 21s, and the karyotype 24,X,+21.可能箭头所指的一对是21号染色体，核型为24,X,+21。
Lower, oöcyte with “predivisional” disomy, showing an additional G-group single chromatid.下方，带有“分裂前”二体的卵母细胞，显示一个额外的G组单染色单体。
The arrowed pair may be chromosome 21s, and the karyotype 24,X,+21cht.箭头所指的一对可能是21号染色体，核型为24,X,+21cht。
Source: From Kamiguchi et al. Chromosomal analysis of unfertilized human oocytes prepared by a gradual fixation-air drying method, Hum Genet 90:533–541, 1993.从Kamiguchi等人所著《采用渐进固定-空气干燥法制备的人未受精卵母细胞的染色体分析》，《人类遗传学》90:533–541，1993年。
Courtesy Y Kamiguchi.Courtesy Y Kamiguchi.
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Origins and Consequences of Chromosome Pathology 37 Figure 3–7.染色体病理的起源与后果 37 图3–7。
Aneuploid gametes producing an aneuploid conceptus (a and b), and aneuploid gametes producing uniparental disomy (c). aneuploid, at least as measured in a population of women presenting to an in vitro fertilization (IVF) clinic (Figure 3–9).非整倍体配子产生非整倍体胚胎（a和b），以及非整倍体配子产生单亲二体（c）。非整倍体，至少在前往体外受精（IVF）诊所的女性群体中测量时如此（图3–9）。
In women aged 28–37 years, nearly half of eggs are disomic or nullisomic, whereas in 38- to 47-year-olds the figure rises to three-quarters (Fragouli et al. 2013).在28–37岁的女性中，近一半的卵子是二体或零体的，而在38–47岁的女性中，这一比例上升到四分之三（Fragouli等人，2013年）。
In a different population—women from teenage to mid-30s presenting for cryopreservation of eggs due to a diagnosis of cancer, and otherwise perhaps more representative, of the general population—Nikiforov et al. (2020) determined a rather smaller fraction, one-third of oöcytes at the second meiotic division being aneuploid.在另一个群体中——因癌症诊断而进行卵子冷冻保存的青少年至35岁左右的女性，这可能更能代表一般人群——Nikiforov等人（2020年）确定了一个较小的比例，即第二次减数分裂的卵母细胞中有三分之一是非整倍体。
If we look at the immediate downstream consequence of these abnormalities, which is to say, the picture in preimplantation embryos at day 3 to 4, again we see a very striking maternal age effect, aneuploidy rates ranging from about 10% to 70% from ages 20s through early 40s (Figure 3–10).如果我们观察这些异常的直接下游后果，即第3至4天植入前胚胎的情况，我们再次看到非常显著的母体年龄效应，非整倍体率从20多岁到40岁出头约为10%到70%（图3–10）。
By day 5—that is, at the appearance of the blastocyst—aneuploidy figures have reduced somewhat, likely reflecting lethality due to the most severe aneuploidies, and range from about a quarter (maternal age under 35) to a half (over age 35) from IVF data (Kubicek et al. 2019).到第5天——即囊胚出现时——非整倍体数据有所下降，可能反映了最严重非整倍体导致的致死性，根据IVF数据，范围从约四分之一（母体年龄低于35岁）到一半（年龄超过35岁）（Kubicek等人，2019年）。
The maternal basis of aneuploidy is again very apparent, with only minor contributions from paternal meiotic error or postmeiotic mitotic error (Figure 3–11).非整倍体的母体基础再次非常明显，父本减数分裂错误或减数分裂后有丝分裂错误的贡献很小（图3–11）。
Certain aneuploidies show predilections for one or other meiotic stage.某些非整倍体对某一减数分裂阶段有偏好。
For example, essentially all trisomy 16 may be due to a maternal meiosis I error, whereas most trisomy 18 reflects meiotic II malsegregation.例如，基本上所有16三体可能源于母本减数分裂I错误，而大多数18三体反映减数分裂II的错误分离。
In those aneuploidies which are capable of carrying on through to birth, it is the classic trisomies of chromosomes 21, 18, 13, and of the sex chromosomes, which have a strong advanced maternal age association, but not triploidy and monosomy X (Elmerdahl Frederiksen et al. 2023). 38 BASIC CONCEPTS Figure 3–9.在那些能够存活到出生的非整倍体中，经典的21、18、13号染色体三体以及性染色体三体与高龄母体年龄有强烈关联，但三倍体和X单体则不然（Elmerdahl Frederiksen等人，2023年）。 38 基本概念 图3–9。
Aneuploidies in Oöcytes of Women of Ages 36–40.36–40岁女性卵母细胞中的非整倍体。
Note: Disomies per chromosome are shown above the 0% baseline, nullisomies below These findings are based on inferences from the analysis of the first and second polar bodies in 676 oöcytes, from women undergoing PGT-A.注：每条染色体的二体显示在0%基线上方，零体显示在下方。这些发现基于对676个卵母细胞的第一和第二极体分析推断得出，这些卵母细胞来自接受PGT-A的女性。
The mirror-like appearance, above and below the line, reflects the agency of meiotic error, with essentially equal likelihoods of the missegregating chromosome going to the egg (for disomy), or to the polar body (for nullisomy); the similar observation of equal numbers of disomies and nullisomies in seen in Oberle et al. (2024).镜面般的外观，线条上下对称，反映了减数分裂错误的作用，错误分离的染色体进入卵子（导致二体）或进入极体（导致零体）的可能性基本相等；Oberle等人（2024）的研究中也观察到二体和零体数量相等的类似现象。
Light green = chromatid gain, darker green = 2-chromatid chromosome gain; Light red = chromatid loss, darker red = 2-chromatid chromosome loss.浅绿色=染色单体增加，深绿色=双染色单体染色体增加；浅红色=染色单体丢失，深红色=双染色单体染色体丢失。
Source: Adapted from P Verdyck et al., Aneuploidy in oocytes from women of advanced maternal age: analysis of the causal meiotic errors and impact on embryo development, Hum Reprod 38:2526–2535, 2023.来源：改编自P Verdyck等人，《高龄女性卵母细胞非整倍体：减数分裂错误的原因分析及其对胚胎发育的影响》，《人类生殖》38:2526–2535，2023年。
Courtesy P Verdyck, and with the permission of Oxford University Press.经P Verdyck许可，并获牛津大学出版社授权。
Figure 3–8.图3–8。
Different Ways in which Meiotic Error may Happen in the Egg.卵子中减数分裂错误可能发生的不同方式。
Notes: Some errors at meiosis I can be corrected at meiosis II, resulting in the egg being euploid.注释：减数分裂I中的某些错误可在减数分裂II中得到纠正，从而使卵子保持整倍体。
In the case of reverse segregation, this correction may be mediated by chromatin threads.在反向分离的情况下，这种纠正可能由染色质丝介导。
Source: From L Wartosch et al., Origins and mechanisms leading to aneuploidy in human eggs, Prenat Diagn 41:620–630, 2021.来源：来自L Wartosch等人，《人类卵子非整倍体的起源与机制》，《产前诊断》41:620–630，2021年。
Courtesy ER Hoffmann, and with the permission of John Wiley and Sons.经ER Hoffmann许可，并获约翰·威利父子出版公司授权。
Origins and Consequences of Chromosome Pathology 39 Spermatogenesis makes very little contribution to meiosis-based aneuploidy (Dviri et al. 2021; Ivanova and Semenova 2023); a reason may be the existence of a postmeiotic checkpoint excluding most aneuploid spermatozoa from full maturation (Uroz and Templado 2012).染色体病理学的起源与后果 39 精子发生对基于减数分裂的非整倍体贡献甚微（Dviri等人，2021年；Ivanova和Semenova，2023年）；其原因可能是存在减数分裂后检查点，阻止大多数非整倍体精子完全成熟（Uroz和Templado，2012年）。
Figure 3–12 sets out the range of abnormality in a very large sample; the comparison with oöcytes (Figure 3–9), in terms of overall fractions, comparing the scales of the y axes, is notable.图3–12展示了一个非常大样本中的异常范围；与卵母细胞（图3–9）在总体比例上的比较，对比y轴刻度，值得注意。
Given the frequency with which nondisjunction happens, it is not at all surprising that instances of multiple aneuploidy are known, the observed numbers during stages of pregnancy reducing as nonviability takes its toll.鉴于不分离发生的频率，出现多重非整倍体的实例并不令人惊讶，随着妊娠阶段推进，由于无法存活，观察到的数量逐渐减少。
In spontaneous abortions toward the end of the first trimester, double autosomal combinations, from simultaneous nondisjunctions, may be seen in the analysis of products of conception Figure 3–10.在妊娠早期末期的自然流产中，通过分析妊娠产物（图3–10），可能观察到由同时发生的不分离导致的双常染色体组合。
Aneuploidy Rates in Day 3 to 4 Embryos.第3至4天胚胎的非整倍体率。
Note: These data were derived from material at day 3 to 4 (the morula stage), through different maternal ages, in patients from an IVF clinic.注：这些数据来源于IVF诊所不同母体年龄的患者在第3至4天（桑椹胚阶段）的材料。
Observe the near straight-line upward slope of the smoothed data (in red) of the graph, attesting to the strong correlation of aneuploidy of the embryo cf. maternal age.观察图中平滑数据（红色）近乎直线的上升斜率，证实了胚胎非整倍体与母体年龄之间的强相关性。
Source: From J Li et al., Chromosome aneuploidy analysis in embryos derived from in vivo and in vitro matured human oocytes, J Transl Med 19:416, 2021.来源：来自J Li等人，《体内和体外成熟人卵母细胞来源胚胎的染色体非整倍体分析》，《转化医学杂志》19:416，2021年。
Courtesy Y Xu, and with the permission of Springer Nature.经Y Xu许可，并获施普林格·自然授权。
Figure 3–11.图3–11。
Aneuploidies in Day 5 to 6 Blastocysts.第5至6天囊胚中的非整倍体。
Note: This is a display of the relative frequencies of the different origins, in day 5-6 blastocysts, of uniform (non-mosaic) aneuploidies of the different chromosomes.注：此图展示了第5至6天囊胚中不同染色体均匀（非嵌合）非整倍体不同来源的相对频率。
Maternal meiotic error is very much the predominant, with only very small contributions due to paternal meiotic error, or from mitotic error in the conceptus.母源减数分裂错误占绝对主导地位，父源减数分裂错误或合子有丝分裂错误仅占极小比例。
These maternal meiotic data closely resemble the similar data in Figure 20–12.这些母源减数分裂数据与图20-12中的类似数据高度吻合。
The data are from an analysis of SNP genotyping from 2,277 trophectoderm biopsies, of which 29% were aneuploid, from women of a wide maternal age range.数据来自对2277份滋养外胚层活检样本的SNP基因分型分析，其中29%为非整倍体，样本来自年龄范围广泛的女性。
Source: From B Rana et al., Identifying parental and cell-division origins of aneuploidy in the human blastocyst, Am J Hum Genet 110:565–574, 2023.来源：摘自B Rana等人，《鉴定人类囊胚非整倍体的亲本和细胞分裂起源》，《美国人类遗传学杂志》110:565–574, 2023。
Courtesy NR Treff, and with the permission of Cell Press.经NR Treff惠允，并获Cell Press许可。
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40 BASIC CONCEPTS (Micale et al. 2010).40 基本概念（Micale等人，2010）。
As for livebirth, the reader with a sense of history will want to review the 48,XXY,+21 case described in Ford et al. (1959); a very few other cases have followed, the most common combination being trisomy 21 along with an additional sex chromosome (Li et al. 2004; Tennakoon et al. 2008).至于活产，有历史感的读者会想回顾Ford等人（1959）描述的48,XXY,+21病例；此后仅有极少数其他病例报道，最常见的组合是21三体伴额外性染色体（Li等人，2004；Tennakoon等人，2008）。
Sequential nondisjunctions at both meiotic divisions could lead to tetrasomy, and this is the basis of some X-chromosomal polysomy (Hassold et al. 1990; Deng et al. 1991).两次减数分裂中连续的不分离可导致四体性，这是某些X染色体多体性的基础（Hassold等人，1990；Deng等人，1991）。
Complete nondisjunction is an expression that could be applied in the case of triploidy—a 69 chromosome count—when this is due to the retention of the polar body within the ovum (Martin et al. 1991).完全性不分离这一表述可用于三倍体（69条染色体）的情况，即由于卵子中极体滞留所致（Martin等人，1991）。
Simultaneous parental nondisjunctions, both gametes being disomic, is rare but not unknown, and is another route to double aneuploidy, and for example Robinson et al. (2001) describe 48,+14[pat],+21[mat] in a spontaneous abortion.父母双方同时发生不分离，即两个配子均为二体，虽罕见但并非未知，这是导致双重非整倍体的另一途径，例如Robinson等人（2001）描述了一例自然流产中的48,+14[父源],+21[母源]。
If one gamete is disomic and the other nullisomic, for the same chromosome, this means that one parent has contributed both members of the homologous pair, and the other none (Figure 3– 7c).如果同一染色体上一个配子为二体而另一个为缺体，则意味着父母一方贡献了同源对的两个成员，而另一方未贡献任何成员（图3-7c）。
This is uniparental disomy due to gametic complementation, an event of extreme rarity.这是由于配子互补导致的单亲二体，属于极为罕见的事件。
Simultaneous errors of nondisjunction and other rearrangement would typically be quite coincidental, such as a child having both XXY Klinefelter syndrome (maternal nondisjunction) and del(15)(q11.2q13) Prader-Willi syndrome (paternal deletion) (Nowaczyk et al. 2004).不分离与其他重排同时发生的错误通常相当偶然，例如一名儿童同时患有XXY克氏综合征（母源不分离）和del(15)(q11.2q13)普拉德-威利综合征（父源缺失）（Nowaczyk等人，2004）。
Causes of Meiotic Malsegregation As discussed above, most aneuploidy due to malsegregation arises in oögenesis. “Quality checking,” which is stringently applied in the male, is poorly effective in the female, and so the maturing of an aneuploid oöcyte is not prevented; and, as Hunt and Hassold (2002) comment, “Nature seems to have erred in putting less protective investment into the more scarce gamete.” A particular vulnerability of maternal meiosis likely lies in the degradation, over time, of factors that underpin the adhesion of the homologous chromatids of the Figure 3–12.减数分裂分离错误的原因 如上所述，大多数由分离错误导致的非整倍体发生于卵子发生过程中。男性中严格应用的“质量检查”在女性中效果不佳，因此无法阻止非整倍体卵母细胞的成熟；正如Hunt和Hassold（2002）所评论的，“大自然似乎犯了错误，将较少的保护性投入放在了更稀缺的配子上。”母源减数分裂的特定脆弱性可能在于，随着时间的推移，支撑图3-12中同源染色单体粘附的因素会退化。
Aneuploidies in Sperm.精子中的非整倍体。
Notes: Disomies per chromosome are shown above the 0‰ baseline, nullisomies below.注：每条染色体的二体性显示在0‰基线上方，缺体性显示在下方。
In most sperm, there is a single abnormality; some may have more than one.大多数精子中仅存在单一异常；部分可能含有多种异常。
Overall, around 0.3% of sperm in this study were nullisomic, and 0.2% disomic; this excess of nullisomy over disomy is also seen in other such studies (García-Mengual et al. 2019).总体而言，本研究中约0.3%的精子为缺体，0.2%为二体；这种缺体多于二体的现象在其他类似研究中也有发现（García-Mengual等人，2019）。
Additionally, 0.4% of sperm were diploid. 99% were normal haploid.此外，0.4%的精子为二倍体，99%为正常单倍体。
These data are derived from ten normozoöspermic men, from whom near a quarter million sperm were analyzed.这些数据来自十名正常精子症男性，共分析了近25万颗精子。
Note the orders of magnitude difference in the y axis measurements of eggs (Figure 3–9 above) cf. sperm: whole numbers % vs. fractions ‰.请注意卵子（图3–9上方）与精子在Y轴测量值上的数量级差异：前者为整数百分比，后者为千分数。
Source: Drawn from data in Table 3 in S Zhu et al., Comprehensive chromosome FISH assessment of sperm aneuploidy in normozoospermic males, J Assist Reprod Genet 39:1887–1900, 2022.来源：根据S Zhu等人《正常精子症男性精子非整倍体的全面染色体FISH评估》中表3数据绘制，J Assist Reprod Genet 39:1887–1900, 2022。
Origins and Consequences of Chromosome Pathology 41 bivalent.染色体病理的起源与后果 41 二价体。
This failure of snug apposition leads the chromosomes to adopt unstable positions when meiosis resumes; or, homologs may become separate from each other, and this then sets the scene for pre-division or for achiasmate nondisjunction (Duncan et al. 2012; Eichenlaub-Ritter 2012).这种紧密贴合的失败导致染色体在减数分裂恢复时处于不稳定位置；或同源染色体彼此分离，从而为提前分裂或无交叉不分离创造条件（Duncan等，2012；Eichenlaub-Ritter，2012）。
This cohesion, or its lack, is the explanation most often raised (Lagirand-Cantaloube et al. 2017).这种黏连或其缺失是最常被提出的解释（Lagirand-Cantaloube等，2017）。
Other possibilities include a role for the spindle apparatus, a component of the cellular machinery which draws chromosomes to their positions in dividing cells, and its compromised function could cause aneuploidy (Mihajlović et al. 2023).其他可能性包括纺锤体装置的作用——该细胞机制组件负责将染色体牵引至分裂细胞中的位置，其功能受损可能导致非整倍体（Mihajlović等，2023）。
While these meiosis-control factors may be the proximate cause of failed disjunction, what background attributes might lead to a loss in its integrity?尽管这些减数分裂控制因素可能是不分离的直接原因，但哪些背景特征会导致其完整性丧失？
Of course, older childbearing age is an obvious answer.当然，高龄生育年龄是一个显而易见的答案。
A very telling insight comes from the work of Battaglia et al. (1996).Battaglia等人（1996）的研究提供了极具启发性的见解。
These investigators sampled oöcytes at meiosis II metaphase from younger (20–25 years) and older (40–45 years) volunteers who were having normal menstrual cycles.这些研究者从月经周期正常的年轻（20–25岁）和年长（40–45岁）志愿者中采集了减数分裂II中期的卵母细胞。
They did not look at individual chromosomes but, rather, at the disposition of the spindle and the metaphase chromosomes as a whole.他们并未观察单个染色体，而是观察纺锤体及中期染色体的整体排列。
They made the most striking findings according to the ages of the women: A symmetrical and neatly arrayed complex was seen in the younger women, while in the older women the spindle was askew, and the chromosomes a-jumble, as shown in Figure 3–13.他们根据女性年龄得出了最显著的发现：年轻女性中可见对称且排列整齐的复合体，而年长女性中纺锤体歪斜、染色体杂乱无章，如图3–13所示。
It is not difficult to accept that this structural disorganization would undermine the capacity of the chromosomes of the oöcyte then to undergo regular segregation (Wasielak-Politowska and Kordowitzki 2022).不难理解，这种结构紊乱会削弱卵母细胞染色体随后进行正常分离的能力（Wasielak-Politowska和Kordowitzki，2022）。
Not that the young are immune.但这并不意味着年轻人免疫。
Fragouli et al. (2006), in a paper dedicated to the memory of the 18-year-old patient whom they had studied, analyzed oöcytes harvested ahead of her chemotherapy for a marrow malignancy which, had she lived, might have enabled fertility.Fragouli等人（2006）在一篇纪念其研究的18岁患者的论文中，分析了该患者因骨髓恶性肿瘤接受化疗前采集的卵母细胞——若她存活，这些卵母细胞本可能实现生育。
Of 11 oöcytes and 7 first polar bodies able to be analyzed, one egg had a single-chromatid X and could have gone on to a monosomy X conception, while another egg was inferred (via its polar body) to have an additional X and 21 chromatid, and the conception could have been 48,XXX,+21.在可分析的11个卵母细胞和7个第一极体中，一个卵子含单染色单体X，可能形成X单体受精卵；另一个卵子（通过其极体推断）含额外X和21染色单体，受精卵可能为48,XXX,+21。
The introductory sentence of this paper is worth quoting: “Humans as a species are not as fertile as other mammals”; and, as already noted, it is in meiosis of the oöcyte that much of this (relative) weakness resides.该论文的开篇语值得引用：“人类作为一个物种，其生育能力不如其他哺乳动物”；如前所述，这种（相对）劣势很大程度上源于卵母细胞的减数分裂。
An alternative to the foregoing meiosis-focused scenarios is to suppose that, at least in some cases, the error in the gamete had arisen at a premeiotic stage, and that the parent is actually a gonadal mosaic for the aneuploidy (see below, PreMeiotic Mitotic Error in the Gamete, and Gonadal Mosaicism).与前述聚焦减数分裂的假说不同，另一种设想是：至少在某些情况下，配子的错误发生在减数分裂前阶段，且亲本实际上是该非整倍体的性腺嵌合体（见下文：配子减数分裂前有丝分裂错误与性腺嵌合现象）。
Meiosis in Chromosomally Abnormal Persons The classic major category is the phenotypically normal person heterozygous for a balanced structural rearrangement (translocation, inversion, and insertion being the main forms), and meiosis can present considerable complication.染色体异常个体的减数分裂 经典的主要类别是表型正常但携带平衡结构重排（易位、倒位和插入为主要形式）的杂合子，其减数分裂可能相当复杂。
A class of increasing importance is the individual who may carry a molecular-defined microdeletion or microduplication, and whose own phenotype may be normal or only mildly or subtly abnormal; and meiosis here is straightforward (although the interpretation of risk is often not, as we discuss below).日益重要的一类是个体可能携带分子定义的微缺失或微重复，其自身表型可能正常或仅轻度或微妙异常；此处的减数分裂过程直接明了（尽管风险解释往往并非如此，我们将在下文讨论）。
Rarely, we see persons who are themselves chromosomally unbalanced with either a full or a partial aneuploidy, and who are clearly phenotypically abnormal, presenting with questions about their reproductive potential.罕见情况下，我们会见到自身染色体不平衡（完全或部分非整倍体）且表型明显异常的个体，这引出了关于其生殖潜能的问题。
We我们
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42 BASIC CONCEPTS Figure 3–13.42 基本概念 图3–13。
Oöcytes in Younger and Older Women.年轻与年长女性的卵母细胞。
Notes: The disposition of the chromosomes at meiosis II in the oöcytes from younger and older women is shown, illustrating what may be the physical basis of the maternal age effect.注释：展示了年轻与年长女性卵母细胞在减数分裂II时染色体的排列情况，说明了母龄效应的可能物理基础。
Meiosis II oöcytes (a) from younger and older women, illustrating what may be the physical basis of the maternal age effect.减数分裂II卵母细胞（a）来自年轻与年长女性，展示了母龄效应的可能物理基础。
The microtubules of the spindle stain green, and the chromosomes stain orange.纺锤体的微管染成绿色，染色体染成橙色。
The tracing (b) identifies these components, and the smooth or wavy lines suggest, respectively, an intact or a degenerating spindle apparatus (the ages of the women indicated).描记图（b）标识了这些成分，平滑或波浪线分别表示完整或退化的纺锤体装置（图中标明了女性年龄）。
The chromosomes are well organized at the metaphase plate at the equator of the cells in the younger women (the 22-year-old’s oöcyte, on the upper left, is viewed on a tilt).在年轻女性中，染色体在细胞赤道板的中期板上排列整齐（左上角22岁女性的卵母细胞呈倾斜视角）。
In contrast, the 40-year-old’s oöcyte shows the chromosomes in disarray.相比之下，40岁女性的卵母细胞显示染色体排列混乱。
The 42-year-old woman’s oöcyte has one chromosome, at the top, dislocated from the metaphase plate, and the disposition of the other chromosomes at the equator is not as regular as in the younger women.42岁女性的卵母细胞中，顶部有一条染色体偏离中期板，其他染色体在赤道板上的排列也不如年轻女性规则。
Source: From Battaglia et al., Influence of maternal age on meiotic spindle assembly in oöcytes from naturally cycling women, Hum Reprod 11: 2217–2222, 1996.来源：摘自Battaglia等人，《母龄对自然周期女性卵母细胞减数分裂纺锤体组装的影响》，《人类生殖》11: 2217–2222, 1996。
Courtesy DE Battaglia, and with the permission of the European Society of Human Reproduction and Embryology and Oxford University Press.经DE Battaglia惠允，并获欧洲人类生殖与胚胎学学会及牛津大学出版社许可。
20 BALANCED CARRIERS OF CLASSIC STRUCTURAL REARRANGEMENTS
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Origins and Consequences of Chromosome Pathology 43 will deal in detail with each situation in separate chapters, but we consider the broad principles here.染色体病理学的起源与后果 43将在各章节详细讨论每种情况，但此处我们考虑总体原则。
BALANCED CARRIERS OF CLASSIC STRUCTURAL REARRANGEMENTS In heterozygotes for some balanced rearrangements involving only small segments, the chromosomes may “ignore” the nonhomologous material they contain, and pair (this is heterosynapsis) and segregate, much as would happen at a normal meiosis.经典结构重排的平衡携带者 在涉及小片段的某些平衡重排杂合子中，染色体可能“忽略”其所含的非同源物质，进行配对（即异源联会）和分离，大致如同正常减数分裂。
In other balanced rearrangements, the inherent tendency to pairing dictates that homologous segments of rearranged chromosomes will align, as well as they are able, in order to achieve full pairing (homosynapsis).在其他平衡重排中，固有的配对倾向要求重排染色体的同源片段尽可能对齐，以实现完全配对（同源联会）。
This may require the chromosome to be something of a contortionist, forming complex configurations such as multivalents and reversed loops.这可能使染色体像杂技演员一样，形成复杂构型，如多价体和反向环。
According to either scenario, the stage is set for the possibility of unbalanced segregation.根据任一情景，不平衡分离的可能性便已埋下伏笔。
The gametes produced—and therefore the conceptuses that arise—are frequently imbalanced.所产生的配子——以及由此形成的受精卵——常常是不平衡的。
In this context, a segmental aneuploidy is usually involved—that is, a part of a chromosome is present in the trisomic or monosomic state; or, quite frequently, a combination of trisomy for one segment and monosomy for another.在这种情况下，通常涉及节段性非整倍体——即染色体的一部分以三体或单体状态存在；或者，相当常见的是，一个节段的三体与另一个节段的单体同时存在。
Partial trisomy and partial monosomy are also referred to as duplication and deletion, respectively.部分三体和部分单体也分别称为重复和缺失。
In some rearrangements, recombination presents a further hazard.在某些重排中，重组会带来进一步的风险。
Inversions and insertions may produce a new recombinant (rec) chromosome that has a different genetic composition from that of the original rearrangement.倒位和插入可能产生一种新的重组染色体，其遗传组成与原始重排不同。
A conceptus forming from a gamete containing it would inevitably be genetically unbalanced.由含有该染色体的配子形成的受精卵将不可避免地遗传不平衡。
CARRIERS OF COPY NUMBER VARIANTS These imbalances, typically detectable only on molecular karyotyping, are small relative to chromosome length, mostly of kilobase size.拷贝数变异的携带者 这些不平衡相对于染色体长度而言较小，通常只能通过分子核型分析检测到，大小多为千碱基级别。
CNVs are not known to interfere with normal cell division; thus, meiosis is typically symmetric, 1:1—an even probability of transmitting the abnormal chromosome (although the resultant phenotype is far less predictable).已知拷贝数变异不会干扰正常细胞分裂；因此，减数分裂通常是对称的，比例为1:1——传递异常染色体的概率相等（尽管最终的表型远非可预测）。
These microdeletions and microduplications are to be distinguished, in practice, from the partial aneuploidies (deletions and duplications) of classical cytogenetics noted above.在实践中，这些微缺失和微重复应与上述经典细胞遗传学中的部分非整倍体（缺失和重复）区分开来。
FULL AND PARTIALLY ANEUPLOID INDIVIDUALS In the individual who him- or herself has a full aneuploidy and in whom gametogenesis is able to proceed, in theory a trivalent may form, or a bivalent and an “independent” univalent.完全和部分非整倍体个体 在自身具有完全非整倍体且能够进行配子发生的个体中，理论上可能形成三价体，或一个二价体加一个“独立”单价体。
Either could lead, effectively, to a 2:1 segregation.这两种情况都可能有效导致2:1分离。
This appears actually to be the case in trisomy 21, whereas in sex chromosomal states (XXX, XXY, and XYY) the “third” chromosome is, as it were, disposed of, and most gametes are normal.这在21三体中似乎确实如此，而在性染色体状态（XXX、XXY和XYY）中，“第三条”染色体实际上被处理掉，大多数配子是正常的。
In the person with a classic partial aneuploidy due to an unbalanced rearranged chromosome, whether 46,(abn) or 47,+(abn), the abnormal chromosome may have an even (or near-even) chance to be transmitted in the gamete. 44 BASIC CONCEPTS Nondisjunction in Mitosis and the Generation of Mosaicism The purpose of a mitotic cell division is faithfully to pass on an intact and complete and balanced copy of the parental cellular genome to the progeny cells.在因不平衡重排染色体（无论是46,(abn)还是47,+(abn)）而患有经典部分非整倍体的人中，异常染色体在配子中传递的概率可能相等（或接近相等）。 44 基本概念 有丝分裂中的不分离与嵌合体的产生 有丝分裂细胞分裂的目的是将亲代细胞基因组完整、完全且平衡的拷贝忠实地传递给子代细胞。
An error in this process can lead to an aneuploid cell.此过程中的错误可能导致非整倍体细胞。
If the error occurs in a mitosis during gametogenesis, mosaicism of the gonad is the consequence, and this is a premeiotic mitotic error.如果错误发生在配子发生过程中的有丝分裂中，则会导致性腺嵌合体，这是一种减数分裂前有丝分裂错误。
An error in early embryogenesis, perhaps as early as the very first mitosis after conception, can lead to a constitutional mosaicism of the embryo, typically comprising a mix of normal and aneuploid cells.早期胚胎发生中的错误，可能早在受精后的第一次有丝分裂中发生，会导致胚胎的体质性嵌合体，通常由正常细胞和非整倍体细胞混合组成。
This is a postmeiotic mitotic error.这是一种减数分裂后有丝分裂错误。
An early error typically leads to a widespread mosaicism, affecting many and possibly all tissues of the embryo.早期错误通常导致广泛的嵌合体，影响胚胎的许多甚至所有组织。
An error in later embryogenesis typically affects a lesser fraction of the soma, and may be restricted to certain tissues, and the expression “low-grade mosaicism” is used.后期胚胎发生中的错误通常影响体细胞中较小的一部分，可能局限于某些组织，并使用“低度嵌合体”这一表述。
If the mosaicism affects a cell line destined to give rise to both some somatic tissue and gonadal tissue, this is somatic-gonadal mosaicism.如果嵌合体影响一个注定要产生某些体细胞组织和性腺组织的细胞系，则称为体细胞-性腺嵌合体。
The mitotic cycle consists of the following sequence: gap-1 period (G1) → synthesis period (S) → gap-2 period (G2) → mitosis (cell division).有丝分裂周期包括以下序列：间隙1期（G1）→ 合成期（S）→ 间隙2期（G2）→ 有丝分裂（细胞分裂）。
The G1 → S → G2 components together comprise the interphase period of the cell cycle.G1期→S期→G2期共同构成细胞周期的间期阶段。
During the S period, the chromosomes replicate their DNA, thus converting from the single-chromatid to the double-chromatid state.在S期，染色体复制其DNA，从而从单染色单体状态转变为双染色单体状态。
Genetically active segments of chromosomes replicate earlier during the S period, while inactive segments, which include almost the entire inactivated X chromosome in the female, are late-replicating.染色体上具有遗传活性的片段在S期较早复制，而失活片段（包括女性体内几乎整条失活的X染色体）则较晚复制。
The cell division period is further subdivided into prometaphase → metaphase → anaphase → telophase.细胞分裂期进一步细分为前中期→中期→后期→末期。
The chromosomes condense to enter prometaphase, and condensation continues into metaphase.染色体凝聚进入前中期，凝聚过程持续到中期。
Metaphase chromosomes align on the equatorial plate (Figure 3–14), and the spindle apparatus becomes attached to the centromere of each chromosome, consisting of its two kinetochores.中期染色体排列在赤道板上（图3-14），纺锤体装置附着于每条染色体的着丝粒上，该着丝粒由两个动粒组成。
Pulled at the kinetochores (centromeres), the chromatids of each chromosome then separate (disjoin) and are drawn in opposite directions (anaphase) and arrive at the opposite poles of the cell (telophase).在动粒（着丝粒）的牵引下，每条染色体的染色单体随后分离（分开），并向相反方向移动（后期），最终到达细胞的两极（末期）。
Then the chromosomes decondense, the nuclear membrane reconstitutes, the cytoplasm constricts and divides, and two daughter cells now exist.然后染色体解凝，核膜重新形成，细胞质收缩并分裂，两个子细胞由此产生。
PreMeiotic Mitotic Error in the Gamete, and Gonadal Mosaicism A mitotic error occurring in a primary gametocyte, oögonium or spermatogonium, prior to its entering into meiosis, can produce an aneuploid cell, which could then lead to a lineage containing this abnormality and comprising a “wedge” or an “island” within the gonad—in other words, gonadal mosaicism with a mix of normal and aneuploid gametocytes.配子减数分裂前有丝分裂错误与性腺嵌合体：在初级配子母细胞、卵原细胞或精原细胞进入减数分裂前发生的有丝分裂错误，可产生非整倍体细胞，进而形成包含此异常的细胞谱系，并在性腺内构成“楔形”或“岛状”区域——换言之，即正常与非整倍体配子母细胞混合存在的性腺嵌合体。
As the abnormal gametocytes enter meiosis, the mature gametes then resulting from them would11 be aneuploid.随着异常配子母细胞进入减数分裂，由此产生的成熟配子将是非整倍体。
Note that the conceptus resulting from such an aneuploid gamete would be uniformly (that is, non-mosaic) aneuploid.由这种非整倍体配子产生的受孕体将是均匀的（即非嵌合体）非整倍体。
We now consider the case in more detail.我们现在更详细地考虑这个情况。
Cells destined to give rise to gametocytes originate from the yolk sac in early embryogenesis and migrate to the gonadal ridge on the dorsal wall of the abdominal cavity, where, along with the supporting cells, they come to comprise the tissue of the gonad (De Felici 2013).在早期胚胎发生过程中，注定形成配子母细胞的细胞起源于卵黄囊，并迁移至腹腔背壁的生殖嵴，在此处与支持细胞共同构成性腺组织（De Felici 2013）。
In doing so, gametocytes 11 Barring a “correction” during meiosis (Maiato and Silva 2023).在此过程中，配子母细胞 11 除非在减数分裂期间发生“修正”（Maiato and Silva 2023）。
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Origins and Consequences of Chromosome Pathology 45 must replicate over and over.染色体病理学的起源与后果 45必须反复复制。
Looking at the male case, going through about 30 cycles of division produces 230 (about 1,000,000,000) progeny spermatogonia, and the potential for error exists at each cell division contributing to this population.在男性案例中，经过大约30次分裂周期会产生2^30（约10亿）个子代精原细胞，而每个细胞分裂过程中都存在产生错误的可能性，这些错误会累积到这一细胞群体中。
These errors could be nondisjunctions, or the production of structural rearrangements.这些错误可能是非分离现象，或是结构重排的产生。
Consider this startling statistic: The total length of the seminiferous tubule in a man is about half a kilometer, a third of a mile (Johnson et al. 1998).考虑这个惊人的统计数据：男性生精小管的总长度约为半公里，即三分之一英里（Johnson等人，1998年）。
If a mutation were to occur in a spermatogonium in, for example, the 20th cycle of division, its progeny would then go through 10 more cycles and comprise 210 (about 1,000) cells.如果在精原细胞中发生突变，例如在第20次分裂周期中，其后代将再经历10次分裂，并产生2¹⁰（约1000）个细胞。
This would be only a millionth (1,000/1,000,000,000) of the ½ km of tubule—a mere ½ mm.这仅占半公里长曲细精管的百万分之一（1000/10亿），即仅半毫米。
So a man mosaic in such a way would have a risk of only one in a million to father a conception with this particular abnormality, given the improbability of the fertilizing sperm coming from this imperfect ½ mm.因此，以这种方式形成嵌合体的男性，其生育带有这种特定异常的后代的风险仅为百万分之一，因为受精精子来自这有缺陷的半毫米区域的可能性极低。
From similar reasoning, a defect arising at the tenth cycle could affect half a meter of tubule and carry a risk of 1 in 1,000.类似推理表明，在第10次分裂周期出现的缺陷可能影响半米长的曲细精管，并带来千分之一的风险。
Oögonia need go through a lesser number of mitotic cycles (about 22), but the same principles broadly apply.卵原细胞需要经历较少的有丝分裂周期（约22次），但相同原理大致适用。
If the error took place in embryonic existence before gonadal precursors had formed, and may thus have involved a cell giving rise to both gonadal and somatic tissue, this is Figure 3–14.如果错误发生在胚胎期性腺前体形成之前，并因此涉及一个同时产生性腺和体细胞组织的细胞，则如图3–14所示。
Mitosis.有丝分裂。
A culinary whimsy.一种烹饪创意。
The cake is a cell about to undergo a mitotic division.蛋糕是一个即将进行有丝分裂的细胞。
The peanut pairs are three double-chromatid chromosomes, submetacentric and metacentric; the reader will need to imagine the other twenty.花生对代表三条双染色单体染色体，分别为亚中着丝粒和中间着丝粒；读者需想象其余二十条。
The other nuts are the spindle mechanism and kinetochores.其他坚果代表纺锤体机制和着丝粒。
Courtesy Dr Nooshin Sheidaei. 46 BASIC CONCEPTS somatic-gonadal mosaicism.图片由Nooshin Sheidaei博士提供。 46 基本概念 体细胞-性腺嵌合体。
If a significant fraction of the soma carries the aneuploid cell line, an abnormal phenotype may result; but if not, the fact of a somatic component may not become known until a gonadal event—that is to say, a child born with the (non-mosaic) aneuploidy—has come to notice (e.g., Figure 3–23).如果体细胞中携带非整倍体细胞系的比例显著，可能导致异常表型；但若非如此，体细胞成分的存在可能直到性腺事件发生——即生出患有（非嵌合型）非整倍体的孩子——才被注意到（例如图3–23）。
Given the huge number of premeiotic mitoses, and, as noted above, opportunity thus for mitotic error, gonadal mosaicism might, in theory, be expected to be common.鉴于减数分裂前有丝分裂次数巨大，且如上所述有丝分裂错误机会众多，理论上性腺嵌合体可能很常见。
This indeed seems to be so, and direct analysis of gametes gives similar results for male and female, with premeiotic aneuploidy12 (disomy or nullisomy) rates around 10% (Ghevaria et al. 2022; Zhu et al. 2022b).13 Findings from family searches for gonadal mosaicism have had mixed results.事实似乎确实如此，对配子的直接分析显示男性和女性结果相似，减数分裂前非整倍体¹²（二体或零体）率约为10%（Ghevaria等，2022；Zhu等，2022b）¹³。针对性腺嵌合体的家族研究结果不一。
Nimmakayalu et al. (2013) report a case from molecular karyotyping: two siblings with macrocephaly and intellectual disability with a 399 kb 19p13.13 microdeletion, this the only case of gonadal mosaicism being recognized in a cohort of 1,800 patients studied.Nimmakayalu等（2013）通过分子核型分析报告一例：两名患有巨头畸形和智力障碍的同胞，携带399 kb的19p13.13微缺失，这是在1800名患者队列中唯一被识别的性腺嵌合体病例。
Campbell et al. (2014) undertook a systematic analysis of parents from a prospectively collected cohort of 100 children with a microdeletion, and they showed four parents to be mosaic for their child’s deletion (the mosaicism level, on blood, was from <1% to 9%).Campbell等（2014）对前瞻性收集的100名微缺失儿童队列的父母进行了系统分析，发现四名父母对其孩子的缺失呈嵌合状态（血液中的嵌合水平从<1%到9%）。
Four out of 100 is a quite surprising number, but perhaps more widely indicative. (These latter cases represent somatic-gonadal mosaicism, and thus could equally have had mention in the following section.) PostMeiotic Mitotic Error and Constitutional Mosaicism A mitotic error can cause phenotypic abnormality by generating, in an initially normal conceptus, an abnormal cell line at some point during early embryogenesis.100例中出现4例相当惊人，但或许更具普遍指示意义。（这些后一病例代表体细胞-性腺嵌合体，因此同样可在下一节提及。）减数分裂后有丝分裂错误与体质性嵌合体 有丝分裂错误可通过在最初正常的受精卵中，于早期胚胎发生过程中产生异常细胞系而导致表型异常。
If we focus on the end result, the feature distinguishing post-conception mitotic from meiotic (or premeiotic mitotic) errors is that the post-conception error typically produces a mosaic conceptus, whereas meiotic/premeiotic errors lead to non-mosaic abnormality.若聚焦最终结果，区分受精后有丝分裂错误与减数分裂（或减数分裂前有丝分裂）错误的特征在于：受精后错误通常产生嵌合型受精卵，而减数分裂/减数分裂前错误导致非嵌合型异常。
We define constitutional chromosomal mosaicism as the coexistence, within the one conceptus, of two (or, rarely, more) distinct cell lines which are otherwise genetically identical except for the chromosomal difference between them, these cell lines having been established by the time that embryonic development is complete (the point at which the embryo becomes a fetus, around eight weeks post-fertilization).我们将体质性染色体嵌合体定义为：在同一受精卵中，两种（或罕见情况下更多）不同的细胞系共存，这些细胞系除染色体差异外遗传上相同，且在胚胎发育完成时（胚胎变为胎儿的节点，约受精后八周）已建立。
Thus, the different cell lines are fixed in the individual and are a part of his or her chromosomal constitution.因此，不同的细胞系在个体中是固定的，并且是其染色体组成的一部分。
The earlier in embryogenesis that a mitotic error occurs, the greater the likelihood for a substantial fraction of the soma to be aneuploid, leading to increasing departure from normality of the phenotype.在胚胎发育过程中，有丝分裂错误发生得越早，体细胞中很大一部分成为非整倍体的可能性就越大，从而导致表型偏离正常程度增加。
But it is probable that many mitotically arising abnormalities lead to cell death, leaving no trace, as we go on to discuss.但许多有丝分裂产生的异常可能导致细胞死亡，不留痕迹，正如我们接下来要讨论的那样。
Mosaicism may involve any type of chromosomal abnormality.嵌合体可能涉及任何类型的染色体异常。
In a large study in Pham et al. (2014), these authors identified 57 cases of somatic mosaicism among just over 10,000 patients, who had presented with a wide range of phenotypic abnormality (and so, naturally, a selected population).在Pham等人（2014年）的一项大型研究中，这些作者在略超过10,000名患者中识别出57例体细胞嵌合体病例，这些患者表现出广泛的表型异常（因此自然属于经过筛选的人群）。
The abnormalities included classic 12 Note that detection of premeiotic aneuploidy requires analysis of immature oöcytes, or alternatively, the analysis of both the metaphase II oöcyte and its corresponding first polar body. 13 Hultén et al. (2013) controversially suggest mitotic errors during ovariogenesis are inevitable and that “most women may be trisomy 21 ovarian mosaics.”异常包括经典12 注意，减数分裂前非整倍体的检测需要分析未成熟卵母细胞，或者替代性地，分析中期II卵母细胞及其对应的第一极体。13 Hultén等人（2013年）有争议地提出，卵巢发生过程中的有丝分裂错误是不可避免的，并且“大多数女性可能是21三体卵巢嵌合体”。
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Origins and Consequences of Chromosome Pathology 47 autosomal and sex chromosomal aneuploidy, isochromosomes, ring chromosomes, marker chromosomes, single del/dups, multiple del/dups, and unbalanced translocations.染色体病理学的起源与后果 47种常染色体和性染色体非整倍体、等臂染色体、环状染色体、标记染色体、单一缺失/重复、多重缺失/重复以及不平衡易位。
The level of mosaicism in these cases ranged from low (5%) to high (80%).这些病例中的嵌合体水平从低（5%）到高（80%）不等。
Mosaicism may affect a cell destined to give rise to both soma and gonad: this is somatic-gonadal mosaicism (quite likely the case in some of the patients in Pham et al. above).嵌合体可能影响一个注定要产生体细胞和生殖细胞的细胞：这就是体细胞-生殖细胞嵌合体（很可能就是上述Pham等人研究中部分患者的情况）。
If the proportion of abnormal cells in the mosaic parent is higher or differently distributed, that parent may manifest some signs of the partial aneuploid state.如果嵌合体亲本中异常细胞的比例更高或分布不同，该亲本可能表现出部分非整倍体状态的某些迹象。
The father reported in Kennedy et al. (2001) had a dup(8)(p23.1p23.1) in mosaic state, in the ratio normal:duplication of 17:8 on blood sampling, and he himself had a heart defect, as did his non-mosaic dup(8) daughter.父亲在Kennedy等人（2001）的研究中报告为嵌合体dup(8)(p23.1p23.1)，血液样本中正常与重复比例为17:8，他本人患有心脏缺陷，其非嵌合体dup(8)女儿也同样患有心脏缺陷。
Her defect was, however, rather more severe than his.然而，她的缺陷比他的更为严重。
Notably, the daughter was described as “achieving top grades in school,” a very unusual phenotypic commentary in a child with a non-mosaic classical chromosome duplication.值得注意的是，女儿被描述为“在学校成绩优异”，这对于一名患有非嵌合型经典染色体重复的儿童来说，是一种非常不寻常的表型描述。
A mother and daughter in Freitas et al. (2012) carried a 6.2 Mb deletion at 2q36.1q36.3, mosaic (~15% on blood) in the mother, non-mosaic in the daughter.Freitas等人（2012）报道的一对母女携带2q36.1q36.3处6.2 Mb的缺失，母亲为嵌合体（血液中约15%），女儿为非嵌合体。
The intellectually disabled daughter presented an obvious facial dysmorphism, but in the mentally normal mother this was very mild, and only appreciated in retrospect.智力障碍的女儿表现出明显的面部畸形，但智力正常的母亲则非常轻微，只有事后回顾才能察觉。
While “clinical chromosomology” is widely seen as a discipline of application particularly to a pediatric or obstetric population, older age groups are beginning to get a look-in.14 The quite common finding of acquired loss of an X or a Y chromosome in an occasional cell in an older female or male population (and more notably in centenarians) may reflect “normal” age-related anaphase lag (Russell et al. 2007).尽管“临床染色体学”通常被视为主要应用于儿科或产科人群的学科，但老年群体也开始受到关注。¹⁴ 在老年女性或男性群体（尤其是百岁老人）的个别细胞中，相当常见的获得性X或Y染色体丢失现象，可能反映了与年龄相关的“正常”后期延迟（Russell等，2007）。
Mosaicism involving an X or an autosome is linked to advanced maternal age, and inferentially to an increased risk for infertility (Kouvidi et al. 2021).涉及X染色体或常染色体的嵌合现象与高龄产妇有关，并推断与不孕风险增加相关（Kouvidi等，2021）。
The potential significance of the observation of mosaic loss of a Y chromosome (mLOY) as a marker of biological aging, and an associated risk for a number of common diseases of aging (Sano et al. 2023; Kuznetsova et al. 2023), is discussed in Chapter 15 (p. 472).关于Y染色体嵌合缺失（mLOY）作为生物衰老标志物及其与多种常见衰老疾病相关风险的潜在意义（Sano等，2023；Kuznetsova等，2023），将在第15章（第472页）讨论。
The suggestion that Alzheimer disease might have a basis in mosaic trisomy 21 or X aneuploidy of some brain tissue is intriguing, but leaves open the question of the time in life at which the putative aneuploid cell line may have become incorporated (Graham et al. 2019; García-González et al. 2023).阿尔茨海默病可能源于某些脑组织的21三体嵌合或X染色体非整倍体的观点引人深思，但未明确假定的非整倍体细胞系可能在生命哪个阶段被整合（Graham等，2019；García-González等，2023）。
The bowel, an organ constantly replenishing its epithelium, accumulates microdeletions and microduplications with age, which are not necessarily harmful (Hsieh et al. 2013).肠道作为不断更新上皮细胞的器官，会随年龄积累微缺失和微重复，这些变化不一定有害（Hsieh等，2013）。
Finally, we make mention, but no more than that, of the role of shortening of the telomeres (the chromosomal “caps”) in aging, and potentially in the diseases of aging (Chakravarti et al. 2021); but this is not what we usually think of as being a part of the repository of classic chromosomal abnormality.最后，我们仅提及端粒（染色体“帽”）缩短在衰老及潜在衰老疾病中的作用（Chakravarti等，2021）；但这通常不被视为经典染色体异常范畴的一部分。
Vulnerability to Error in the First Few Mitoses in a Euploid Zygote or Early Embryo The first few mitotic divisions from the normal (46,N) one-cell zygote, the fertilized egg, are particularly vulnerable to error, and especially the very first, the number-one 14 Actually, the classic example of disease due to acquired somatic chromosomal mosaicism is, of course, cancer, usually an age-related condition; and a textbook of much larger size than this one would be needed to review the role of tissue-confined aneuploidy apropos (Oromendia and Amon 2014); we make no further mention here. 48 BASIC CONCEPTS mitosis (Currie et al. 2022).整倍体合子或早期胚胎最初几次有丝分裂的易错性 正常（46,N）单细胞合子（受精卵）的最初几次有丝分裂特别容易出错，尤其是第一次分裂。实际上，获得性体细胞染色体嵌合导致的疾病经典例子当然是癌症，这通常与年龄相关；要全面评述组织局限非整倍体的作用，需要比本书规模大得多的教科书（Oromendia和Amon，2014）；此处不再赘述。 48 基本概念 有丝分裂（Currie等，2022）。
Thus it is that the embryo is at risk of constitutional mosaicism.因此，胚胎存在发生结构性嵌合的风险。
The coexistence of a normal and an aneuploid cell line is called diploid-aneuploid mosaicism.正常细胞系与非整倍体细胞系共存称为二倍体-非整倍体嵌合。
Insight into this vulnerability has come from experience in the IVF laboratory (Chapter 23), and retrospective inferences can be drawn from study of mosaic individuals.对这种易错性的认识来自体外受精实验室的经验（第23章），并可通过回顾性推断研究嵌合个体。
In an initially normal zygote, a mitotic nondisjunction at the very first cell division would generate mosaicism for a trisomic and a concomitant monosomic line; in the next few mitoses, the monosomic cell line would likely fail, leaving an embryo with a non-mosaic trisomy.在最初正常的合子中，第一次细胞分裂时发生有丝分裂不分离将产生三体与伴随单体细胞系的嵌合；在随后几次有丝分裂中，单体细胞系可能失败，留下非嵌合三体胚胎。
A mitotic error occurring in one of the two cells at the next, the second mitosis, would produce mosaicism with, as well as a trisomic and a monosomic cell line, a normal cell line (Figure 3–15a).第二次有丝分裂中两个细胞之一发生错误，将产生包含三体、单体及正常细胞系的嵌合（图3–15a）。
In mosaicism due to autosomal nondisjunction, growth of a monosomic cell line is severely compromised, and it will likely die out at a very early stage, leaving just the trisomic cell line (mitosis no. 1 error) or normal and trisomic cell lines (mitosis no. 2 et seq. error) to continue growing.15 The picture may be different with the X chromosome (see below).在常染色体不分离导致的嵌合中，单体细胞系的生长严重受限，很可能在极早期消亡，仅留下三体细胞系（第一次有丝分裂错误）或正常与三体细胞系（第二次及后续有丝分裂错误）继续生长。15 X染色体的情况可能不同（见下文）。
Surprisingly large fractions, a quarter to a third, of cleavage-stage embryos (day 3) subjected to preimplantation genetic testing (PGT) are chromosomally mosaic, typically with complete aneuploidies (at least in a population of usually older women presenting at an IVF clinic).令人惊讶的是，接受植入前遗传学检测（PGT）的卵裂期胚胎（第3天）中，有四分之一到三分之一存在染色体嵌合，通常表现为完全非整倍体（至少在IVF诊所的通常高龄女性群体中）。
Mosaicisms are frequently observed at day 4 (the morula); this stage is seen as a watershed, and very many aneuploid conceptuses arrest development here (Mertzanidou et al. 2013).嵌合现象在第4天（桑椹胚）经常被观察到；这一阶段被视为分水岭，许多非整倍体胚胎在此停止发育（Mertzanidou等，2013）。
At the blastocyst stage, the study of entire embryos allows the analysis of more than 50 single cells per embryo,16 and at this timeframe even higher levels of mosaicism are revealed: around 80% of embryos contain at least some cells with numerical and/or structural abnormalities, with the majority being euploid-aneuploid mosaic (Chavli et al. 2024).在囊胚阶段，对整个胚胎的研究可分析每个胚胎超过50个单细胞，16在此时间点甚至发现更高水平的嵌合：约80%的胚胎含有至少部分存在数目和/或结构异常的细胞，其中大多数为整倍体-非整倍体嵌合（Chavli等，2024）。
Survival or demise of these very early mosaic diploid-aneuploid conceptuses will depend upon the particular aneuploid chromosome involved, and the extent within the cell mass of the normal cell line.这些极早期嵌合二倍体-非整倍体胚胎的存活或消亡取决于所涉及的具体非整倍体染色体以及正常细胞系在细胞团中的比例。
Particularly where a “large”17 aneuploid chromosome is involved, and if it comprises a substantial fraction of the soma, a morula or blastocyst will early succumb and fail to implant or, if proceeding to an embryonic stage, will subsequently miscarry.特别是当涉及“大”17非整倍体染色体且其占体细胞显著比例时，桑椹胚或囊胚将早期死亡并无法着床，或若进入胚胎阶段则会随后流产。
But “small” chromosome mosaicisms may survive, and mosaic Down syndrome with the karyotype 46,N/47,+21 is the classic example. 15 A very rare example of autosomal monosomy/disomy/trisomy mosaicism was identified in the abnormal baby reported in Stefanou et al. (2006), mentioned below.但“小”染色体嵌合可能存活，核型为46,N/47,+21的嵌合唐氏综合征是经典例子。15 在Stefanou等（2006）报道的异常婴儿中发现了极罕见的常染色体单亲二体/二体/三体嵌合，下文将提及。
Only one cell in 200 on blood showed 47,XY,+20, and disomy was demonstrated on buccal mucosal FISH and skin fibroblast analysis, but 39/50 cells from urinary sediment were monosomic. 16 In these experiments, embryos are destroyed, as distinct from embryo biopsy in PGT, where only 5–10 cells are removed. 17 A “large” chromosome refers to size but also to content, in terms of the number, and roles, of the genes therein (Figure 1–4).血液中每200个细胞仅1个显示47,XY,+20，颊黏膜FISH和皮肤成纤维细胞分析显示二体，但尿沉渣中39/50个细胞为单体。16 在这些实验中，胚胎被破坏，不同于PGT中仅移除5–10个细胞的胚胎活检。17 “大”染色体指大小，也指其中基因的数量和功能（图1–4）。
In this context, chromosome 19, while of short length, is particularly gene-dense and so could be considered functionally large.在此背景下，19号染色体虽长度较短，但基因密度特别高，因此可视为功能上的大染色体。
Chromosome 21 is “small,” both in terms of length and in being gene-sparse.染色体21号在长度上“小”，且基因稀疏。
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Origins and Consequences of Chromosome Pathology 49 In one particular well-known survivable autosomal aneuploidy, trisomy 8 mosaicism, somatic nondisjunction accounts for practically all cases (Karadima et al. 1998).染色体病理学的起源与后果 49 在一个特别著名的可存活常染色体非整倍体——8号三体嵌合体中，体细胞不分离几乎解释了所有病例（Karadima等，1998）。
Insight into the timing of the abnormality can be gained from inference in the study of mosaic individuals, and X chromosome mosaicism has been particularly informative.对异常发生时间的洞察可以通过对嵌合体个体的研究推断获得，而X染色体嵌合现象尤其具有信息价值。
An aberrant mitosis involving the X chromosome, in an initially 46,XX zygote, may generate X and XXX cell lines, both of which would be survivable.涉及X染色体的异常有丝分裂，在最初为46,XX的受精卵中，可能产生X和XXX细胞系，这两种细胞系均能存活。
If this happens at the first mitosis, X/XXX mosaicism would result.如果这发生在第一次有丝分裂时，就会导致X/XXX嵌合体。
If at any later mitosis, a normal cell line would exist, and the mosaic state would be X/XX/XXX (Essouabni et al. 2023) (Figure 3–15b).如果在后续的任何有丝分裂中，存在一条正常的细胞系，那么嵌合状态将为X/XX/XXX（Essouabni等人，2023）（图3–15b）。
The same can happen in a 46,XY zygote, with an X/XYY or an X/XY/XYY mosaicism resulting (the gender in the embryo being determined according to the sex chromosome composition of gonadal tissue).在46,XY受精卵中也可能发生同样情况，导致X/XYY或X/XY/XYY嵌合体（胚胎性别根据性腺组织的性染色体组成决定）。
Similarly, Jacobs et al. (1997), in a study of Turner syndrome, observed that patients with Xq isochromosome mosaicism hardly ever have a Figure 3–15.类似地，Jacobs等人（1997年）在一项关于特纳综合征的研究中观察到，带有Xq等臂染色体嵌合体的患者几乎从未出现过图3–15。
The Generation of Mosaicism. (a) Postzygotic nondisjunction in an initially normal conceptus.嵌合体的产生。(a) 最初正常的受精卵在合子后发生不分离。
In this example, one cell line (monosomic 21) is subsequently lost, with the final karyotype 46,N/47,+21. (b) Postzygotic nondisjunction in an initially normal 46,XX conceptus, resulting in 45, X/46,XX/47,XXX mosaicism. (c) Postzygotic anaphase lag in an initially abnormal 47,+21 conceptus; this leads to a “corrected,” or “rescued,” normal cell line. 50 BASIC CONCEPTS 46,XX cell line: Most are 45,X/46,X,i(Xq).随后丢失了一个细胞系（单体21），最终核型为46,N/47,+21。(b) 最初正常的46,XX受精卵发生合子后不分离，导致45,X/46,XX/47,XXX嵌合体。(c) 最初异常的47,+21受精卵发生合子后后期延迟；这导致“校正”或“拯救”的正常细胞系。 50 基本概念 46,XX细胞系：大多数为45,X/46,X,i(Xq)。
This is what would be expected if the error happened at the very first mitosis of the initially 46,XX zygote.这是如果错误发生在最初46,XX受精卵的第一次有丝分裂时所预期的情况。
If it happened at the next two or three divisions, a 46,XX cell line would also have been present, and thus three cell lines, 45,X/46,XX/46,X,i(Xq).如果发生在接下来的两三个分裂中，也会出现46,XX细胞系，从而形成三种细胞系：45,X/46,XX/46,X,i(Xq)。
The presence of three cell lines in Stefanou et al. (2006), who describe an abnormal infant with diploid/aneuploid trisomy 20 mosaicism on blood, but with a monosomic 20 cell line identified in urinary epithelial cells, similarly allows the inference of an initiating error at, or a little later than, the second mitosis.Stefanou等人（2006）描述了在血液中具有二倍体/非整倍体20号染色体三体嵌合体、但在尿路上皮细胞中鉴定出20号染色体单体细胞系的异常婴儿，其中存在三种细胞系，同样可以推断初始错误发生在第二次有丝分裂时或稍晚阶段。
Actually, about 5% of standard apparently non-mosaic 47,+21 is due to a postmeiotic mitotic defect from a 46,N zygote (Antonarakis et al. 1993), with the “third” chromosome 21 equally likely to be maternal or paternal.实际上，约5%的典型非嵌合型47,+21是由46,N合子减数分裂后有丝分裂缺陷所致（Antonarakis et al. 1993），其中“第三条”21号染色体来自母亲或父亲的可能性相等。
In 3% of apparently non-mosaic 47,XXY and 9% of 47,XXX, the error was post-zygotic, presumably prior to the formation of the inner cell mass18 (MacDonald et al. 1994).在3%的显然非嵌合型47,XXY和9%的47,XXX病例中，错误发生在受精后，推测是在内细胞团形成之前18（MacDonald等人，1994年）。
As noted above, the nature of the mosaicism can indicate the likely time of its generation.如上所述，嵌合体的性质可以提示其产生的大致时间。
More than one mitotic error can happen, separate in time and place; for example, DeBrasi et al. (1995) identified concomitant 45,X, 46,X,+8, and 47,XX,+8 in a woman with clinical features of both trisomy 8 and Turner syndrome, in whom the molecular study supported the hypothesis of an originally 46,XX conception.多个有丝分裂错误可能发生，在时间和空间上彼此独立；例如，DeBrasi等人（1995）在一名同时具有8三体和特纳综合征临床特征的女性中发现了45,X、46,X,+8和47,XX,+8的共存，分子研究支持其最初为46,XX受精卵的假说。
Mosaicism Arising from Error at Later Mitoses in a Euploid Embryo The categories of mosaicism described above are associated with phenotypes of varying degrees of severity, and with the mitotic event having caused the mosaicism of early occurrence during embryogenesis.后期有丝分裂错误导致的嵌合体（发生于整倍体胚胎中）上述描述的嵌合体类型与不同程度严重性的表型相关，并且与胚胎发生早期引起嵌合体的有丝分裂事件有关。
But if the aberrant mitosis takes place later in embryogenesis, perhaps some thousands or millions of cell divisions along the way to the establishment of the fetal, and thus, eventually, post-natal anatomy, the effect upon the phenotype may be minimal, indiscernible, or without any effect at all.19 Perhaps, as we now go on to discuss, every apparently 46,XX or 46,XY person is, somewhere in their anatomy, a mosaic.但如果异常有丝分裂发生在胚胎发生后期，也许是在建立胎儿（进而最终形成出生后解剖结构）的过程中经历了数千或数百万次细胞分裂之后，其对表型的影响可能极小、难以察觉，甚至完全没有影响。19 或许，正如我们接下来要讨论的，每一个看似46,XX或46,XY的人，在其身体的某个部位都是一个嵌合体。
Consider the following.考虑以下情况。
A classic chromosome test on any normal person—a routine analysis from a sample of peripheral blood, or from a “spit” sample—would probably get a normal result (46,N).对任何正常人进行经典的染色体检测——对外周血样本或“唾液”样本进行常规分析——可能会得到正常结果（46,N）。
We would conclude from an analysis of a dozen or so cells from one particular tissue that the rest of the soma is also 46,N.我们会根据对某一特定组织中十几个细胞的分析，推断其余体细胞也是46,N。
In most of the person’s tissue, this will be truly the case.在人体的大部分组织中，这确实是事实。
But the body comprises a vast number of cells—ten trillion (1013) or so—which required a vast number of mitoses for their generation.但人体由数量庞大的细胞组成——大约十万亿（10¹³）个——这些细胞的产生需要大量的有丝分裂。
The dozen cells checked in the laboratory are only a ten-billionth of a percent of all the person’s cells, and we routinely (and, for practical purposes, not unreasonably) regard this minute fraction as a valid representative of the remaining 99.9999999999%.实验室检查的十几个细胞仅占人体所有细胞的百亿分之一，而我们通常（出于实际目的，这并非不合理）将这极小部分视为其余99.9999999999%细胞的有效代表。
Notwithstanding, we can surely suppose that one or more errors will have happened during one or some of the many mitoses, and these will have produced a chromosomally abnormal cell line, and the person is really a chromosomal mosaic.尽管如此，我们当然可以假设，在众多有丝分裂中的一次或几次中会发生一个或多个错误，这些错误会产生一条染色体异常的细胞系，那么这个人实际上就是一个染色体嵌合体。
It seems plausible to 18 The “inner cell mass” is seen as a clump of cells on part of the inner wall of the blastocyst, and these cells are destined to form the embryo (Figure 23–6).这似乎合理。18 “内细胞团”被视为囊胚内壁一部分上的一团细胞，这些细胞将发育成胚胎（图23–6）。
The remaining cells, comprising the shell of the blastocyst, are trophoblasts, and will form the placenta. 19 But not overlooking, as noted above, that some chromosomal mosaicisms of restricted extent, or of late acquisition, can lead to certain adult-onset diseases.构成囊胚外壳的其余细胞是滋养层细胞，将形成胎盘。19 但不可忽视的是，如上所述，某些范围有限或后期获得的染色体嵌合体可能导致某些成人期发病的疾病。
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Origins and Consequences of Chromosome Pathology 51 imagine that unrecognized islets of mosaicism, involving a tiny number of cells—only a few thousand, perhaps—could well be a frequent state.染色体病理学的起源与后果 51 可以想象，未被识别的嵌合体小岛——可能仅涉及数千个细胞——很可能是一种常见状态。
Almost certainly, somewhere in their soma, everyone may be such a mosaic; but this fascinating academic matter is not a question of much practical relevance in the genetic counseling clinic.几乎可以肯定，在每个人身体的某个部位，都可能存在这样的嵌合体；但这个引人入胜的学术问题在遗传咨询门诊中并非具有太多实际意义的问题。
Classical cytogenetics can (if the tested tissue is representative) show mosaicism unequivocally, with the recognition of two different karyotypes, but this is dependent on there being enough cells in the less frequent line for the observation to be made.经典细胞遗传学（若检测组织具有代表性）可明确显示嵌合现象，识别出两种不同的核型，但这取决于数量较少的细胞系中是否有足够多的细胞可供观察。
In molecular karyotyping, detection is a subtler exercise, and it is based on an appreciation of a quantitative shift in the log2 graph, or, if single nucleotide polymorphism array is the methodology, the genotyping pattern may be revealing; but in principle, mosaicism that might otherwise have slipped through on classical analysis can be picked up (Repnikova et al. 2012).在分子核型分析中，检测是一项更为精细的工作，它基于对log2图中定量变化的判断，或者，如果采用单核苷酸多态性阵列方法，基因分型模式可能会揭示问题；但原则上，那些在传统分析中可能被遗漏的嵌合体可以被发现（Repnikova等人，2012年）。
The practicalities of this question are discussed below, Tissue Sampling in the Detection of Mosaicism.该问题的实际操作细节如下，组织取样在嵌合体检测中的应用。
Mosaicism Arising from Error in an Aneuploid Zygote or Embryo Nondisjunction can occur in a post-zygotic mitosis in a conceptus that is initially trisomic for an autosome (for example, 47,+21).嵌合体源于非整倍体合子或胚胎中的错误
Thus, one copy of the homolog in question is lost.因此，所讨论的那个同源拷贝丢失了。
The same result may be due to the mechanism of anaphase lag.20 This converts the trisomy in this cell to 46,N and is sometimes referred to as “correction” or “rescue.” Its descendant cells are 46,N, and the karyotype of the conceptus is, for example, 47,+21/46,N (Figure 3–15c).相同的结果可能是由于后期延迟机制所致。20 这使该细胞中的三体性转变为46,N，有时被称为“校正”或“拯救”。其子代细胞为46,N，而胚胎的核型例如为47,+21/46,N（图3–15c）。
Most mosaic trisomy/disomy 13, 18, 21, and X, arises in this way: for example, 47,XXY → 46,XY/47,XXY (Robinson et al. 1995).大多数嵌合体三体/二体13、18、21和X染色体以此方式产生：例如，47,XXY → 46,XY/47,XXY（Robinson等，1995）。
A conceptus with what might be called interchange tertiary trisomy—that is, a 47-chromosome count, with the two translocation chromosomes and an additional copy of one of the derivative chromosomes—might generate a cell line with the balanced state, if one of the derivatives is lost post-zygotically.一个具有所谓互换型三级三体——即染色体数为47，包含两条易位染色体及其中一条衍生染色体的额外拷贝——的受孕体，若在合子后丢失其中一条衍生染色体，则可能产生一个处于平衡状态的细胞系。
Thus, a zygote with, for example, a 47,t(1;2),+der(1) karyotype might acquire a cell line with 46,t(1;2).因此，一个核型为47,t(1;2),+der(1)的受精卵可能会产生一个核型为46,t(1;2)的细胞系。
If this cell line included blood-forming tissue, but if much of the soma otherwise consisted of cells with the unbalanced state, a phenotypically abnormal child could have, on blood sampling, a balanced translocation karyotype.如果该细胞系包含造血组织，但如果大部分体细胞由不平衡状态的细胞组成，那么一个表型异常的孩子在血液采样时可能表现出平衡易位的核型。
Such a case is presented in Dufke et al. (2001) concerning an abnormal child who, on blood, had a familial balanced karyotype 46,t(17;22), but who on skin biopsy karyotyped 47,der(22)t(17;22), and was thus shown to be duplicated for segments of 17 and 22.Dufke等人（2001）报告了这样一个病例：一名异常儿童，其血液检查显示家族性平衡核型46,t(17;22)，但皮肤活检核型为47,der(22)t(17;22)，因此表明该儿童存在17号和22号染色体片段的重复。
These authors speculate that this scenario might be a rare contributor to the apparent slight excess of abnormal children among the balanced carrier offspring of translocation carrier parents (p. 123).这些作者推测，这种情况可能是易位携带者父母的后代中，平衡携带者子女出现异常儿童比例略高的一个罕见因素（第123页）。
Gonadal mosaicism can arise due to this mechanism, and again the classic example comes from mosaic trisomy 21, in which a 47,+21 embryo at a very early post-zygotic 20 In this latter case, the chromosome fails to connect to the spindle apparatus, or is tardily drawn to its pole, and fails to be included in the reforming nuclear membrane.性腺嵌合体可能由此机制产生，经典案例同样来自嵌合型21三体，即极早期合子后阶段形成的47,+21胚胎。
On its own in the cytoplasm, it will form a micronucleus and soon be lost. 52 BASIC CONCEPTS stage discards the extra chromosome in one cell, thus giving a 46,N lineage.在细胞质中单独存在时，它会形成一个微核并很快丢失。 52 基本概念 阶段丢弃一个细胞中的多余染色体，从而产生46,N谱系。
This 46,N line then contributes to most tissues, and an apparently normal physical phenotype results; but the gonad is not so fortunate, as it were, and may receive a larger fraction of 47,+21 cells (Kovaleva 2010).这条46,N系随后对大多数组织有贡献，并产生看似正常的身体表型；但性腺就没那么幸运了，它可能接收更大比例的47,+21细胞（Kovaleva 2010）。
A clinical observation supporting this conclusion is that the low-level mosaic mothers (who had presented due to their having had a non-mosaic Down syndrome child) are of a typical maternal age range, whereas their mothers— the grandmothers of the Down syndrome children—were of older maternal age at the time their daughters had been born.支持这一结论的临床观察是，低水平嵌合体母亲（因曾生育非嵌合体唐氏综合征患儿而就诊）的生育年龄处于典型范围，而她们的母亲——即唐氏综合征患儿的外祖母——在生育这些女儿时则属于高龄产妇。
This is consistent with their daughters having been conceived as (maternal-age-influenced) trisomy 21, but subsequently, at least in their soma, “corrected.” Post-zygotic “Correction” of Aneuploidy and Uniparental Disomy.这与他们的女儿被怀上时是（受母亲年龄影响的）21三体综合征一致，但随后，至少在其体细胞中，得到了“纠正”。合子后非整倍体与单亲二体的“纠正”。
If the conversion of trisomy to disomy occurs prior to the formation of the inner cell mass, and if the 46,N line then gives rise to the inner cell mass, the embryo will be non-mosaic 46,N.如果三体转变为二体发生在内细胞团形成之前，并且随后46,N细胞系形成了内细胞团，那么胚胎将是非嵌合体46,N。
According to which one of the three chromosomes was lost, normal biparental disomy in the embryo could be restored, or uniparental disomy (UPD) could result (Figure 3–16).根据丢失的是三条染色体中的哪一条，胚胎中正常的双亲二体性可能得以恢复，也可能导致单亲二体性（UPD）（图3–16）。
This is much the usual mechanism of formation of UPD.这是UPD形成的常见机制。
It is at prenatal diagnosis, typically, that the fact of this rescue mechanism comes to be discovered, with trisomy seen at chorionic villus sampling (CVS) and disomy at a subsequent amniocentesis (Sirchia et al. 1998).通常在产前诊断中，这种补救机制才会被发现，例如在绒毛膜取样（CVS）中检测到三体，而在后续的羊膜穿刺中检测到二体（Sirchia et al. 1998）。
Chromosome 15 is of particular concern, and Purvis-Smith et al. (1992) and Cassidy et al. (1992) provide historic illustrations in pregnancies showing 47,+15 at CVS, with conversion to 46,N at amniocentesis— but the infants had UPD(15)mat, and so they were born with Prader-Willi syndrome.15号染色体尤其值得关注，Purvis-Smith等人（1992）和Cassidy等人（1992）提供了历史上的案例：在CVS中显示47,+15，而在羊膜穿刺中转为46,N——但婴儿患有母源UPD(15)，因此出生时患有普拉德-威利综合征。
A contemporary example is the diagnosis of UPD(15)mat following the detection of trisomy 15 at noninvasive prenatal testing (NIPT) (Hong et al. 2023).一个当代的例子是在无创产前检测（NIPT）中发现15号染色体三体后诊断出母源UPD(15)（Hong et al. 2023）。
An inference of “rescue” may be made in the case of UPD discovered because of isozygosity for a recessive gene, and an example of this is deafness due to the connexin-26 gene.当UPD因隐性基因的纯合性而被发现时，可以推断出“补救”机制，一个例子是由connexin-26基因导致的耳聋。
Yan et al. (2007) report a child presenting with deafness due to homozygosity for the common 35delG mutation, for which his father, but not his mother, was a carrier.Yan等人（2007）报告了一名儿童因常见35delG突变的纯合性而出现耳聋，其父亲是该突变的携带者，而母亲不是。
As it transpired, the child had UPD(13)pat, with isodisomic and heterodisomic segments of chromosome 13.结果发现，该儿童患有父源UPD(13)，其13号染色体上存在等位同源和异位同源片段。
The segment in 13q12.1, which contains the connexin-26 locus, was one of the regions of isodisomy.包含connexin-26基因座的13q12.1片段是等位同源区域之一。
Quite possibly, this had been a trisomic 13 conception but rescued due to discarding one of the chromosomes, which happened to be the maternal chromosome 13.很可能，这最初是一个13号染色体三体的受精卵，但由于丢弃了其中一条染色体（恰好是母源13号染色体）而得到补救。
Had it not been for the coincidence of the father’s heterozygosity for the 35delG mutation, the rescue would have been entirely successful.如果不是因为父亲恰好是35delG突变的杂合子，这次补救本会完全成功。
Post-zygotic correction can also happen in the other direction, as it were: to convert a monosomic zygote into a disomic one.受精后的校正也可能朝另一个方向发生：将单体的受精卵转变为二体的受精卵。
It is very rarely recognized (Schinzel et al. 1993).这种情况非常罕见（Schinzel et al. 1993）。
Quan et al. (1997) report a girl, 46,XX, with Duchenne muscular dystrophy due to a homozygous deletion of exon 50 of the dystrophin gene.Quan等人（1997）报告了一名46,XX的女孩，因dystrophin基因第50号外显子的纯合缺失而患有杜氏肌营养不良症。
She had homozygosity of the X chromosome for all of the tested marker loci, apparently a complete maternal uniparental isodisomy X.她的X染色体在所有检测的标记位点上均为纯合，显然是完整的母源单亲等位同源X染色体。
Even a meiosis II nondisjunction would likely have had some heterozygosity, due to recombination at meiosis I; and so Quan and colleagues propose a mitotic mechanism.即使是减数第二次分裂的不分离，由于减数第一次分裂中的重组，也可能存在一些杂合性；因此Quan及其同事提出了一种有丝分裂机制。
A 45,X0 conception, from a “22,0” sperm + 23,X egg at syngamy, underwent duplication, or possibly nondisjunction, of the single X chromosome.一个45,X0的受精卵，由“22,0”精子与23,X卵子在合子形成时结合，随后经历了单条X染色体的复制，或可能是不分离。
Unfortunately, this X chromosome carried a de novo Duchenne mutation.不幸的是，这条X染色体携带了一个新发的杜氏突变。
25 BALANCED CARRIERS OF CLASSIC STRUCTURAL REARRANGEMENTS
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Origins and Consequences of Chromosome Pathology 53 Mosaicism Due to Somatic Recombination in Homologs Genetic exchange can take place as a normal event during a mitotic cycle, involving either the pair of homologous chromosomes or the sister chromatids of one chromosome.染色体病理学的起源与后果 53 因同源染色体体细胞重组导致的嵌合体 遗传交换可以在有丝分裂周期中作为正常事件发生，涉及一对同源染色体或一条染色体的姐妹染色单体。
The cytogenetic demonstration of sister chromatid exchange (SCE) is rather dramatic (Figure 16–3).姐妹染色单体交换（SCE）的细胞遗传学展示相当显著（图16–3）。
Should the SCE be unequal, tandem duplication and deletion lines may be generated.如果SCE不等，可能会产生串联重复和缺失系。
If the deletion line is lost, a normal/duplication mosaicism results (Rauen Figure 3–16.如果缺失系丢失，则会导致正常/重复嵌合体（Rauen图3–16）。
Uniparental disomy from “correction” of a trisomic conceptus by loss of a homolog.通过丢失同源染色体“纠正”三体合子导致的单亲二体性。
Nondisjunction* at meiosis I, followed by postzygotic loss** of one homolog, causes uniparental heterodisomy. (If, for example, this were chromosome 15, and the meiotic nondisjunction occurred in the mother, the child would have Prader-Willi syndrome.) Nondisjunction at meiosis II would cause uniparental isodisomy. 54 BASIC CONCEPTS et al. 2001).减数分裂I的非整倍性*，随后合子后丢失**一个同源染色体，导致单亲异二体性。（例如，如果这是15号染色体，且减数分裂非整倍性发生在母亲身上，孩子将患有普拉德-威利综合征。）减数分裂II的非整倍性会导致单亲同二体性。 54 基本概念 等，2001）。
According to the somatic extent of the abnormal cell line, the phenotype may or may not be affected.根据异常细胞系的体细胞范围，表型可能受影响也可能不受影响。
CHIMERISM Chimerism, which is to be distinguished from mosaicism, is the coexistence of more than one cell line in an individual due to the union of two originally separate (“sibling”) conceptions (Chen et al. 2013f; Madan 2020).21 It could be imagined that dizygotic twin blastocysts happen to make contact and then fuse, and this may be the more typical scenario.嵌合体 嵌合体（需与嵌合现象区分）是由于两个原本独立的（“同胞”）受精卵融合（Chen等，2013f；Madan，2020）21而导致个体内存在多个细胞系。可以想象，异卵双胞胎囊胚偶然接触并融合，这可能是更典型的情况。
Since four gametes will have contributed to the person, we may hear the expression “tetragametic” chimerism.由于四个配子将贡献给这个人，我们可能会听到“四配子”嵌合体的说法。
Alternatively, but rarely, there might have been two sperm fertilizing an ovum and a polar body.另一种罕见情况是，两个精子使一个卵子和一个极体受精。
A 46,XX//46,XX or 46,XY//46,XY chimera would most probably present as a normal female or male, whereas 46,XX//46,XY could manifest an abnormality of sexual differentiation (Wimmer et al. 2022).46,XX//46,XX或46,XY//46,XY嵌合体很可能表现为正常女性或男性，而46,XX//46,XY可能表现为性分化异常（Wimmer等，2022）。
The discovery of chimerism can cast a most remarkable light in certain cases in which parenthood is being tested.在某些亲子鉴定案例中，嵌合体的发现可能带来极其显著的影响。
A mother apparently “could not have been” the mother of two of her three sons, when she and the family underwent HLA (immune histocompatibility) testing ahead of a planned kidney transplant.一位母亲在计划肾移植前与家人进行HLA（免疫组织相容性）检测时，显然“不可能是”她三个儿子中两个的母亲。
But it transpired that she was a tetragametic 46,XX//46,XX chimera.但结果发现她是一个四配子46,XX//46,XX嵌合体。
Her ovaries presumably comprised tissue from both fused conceptuses, but blood-forming tissue came from only one.她的卵巢可能包含来自两个融合受精卵的组织，但造血组织仅来自其中一个。
Thus, she could have children who had neither of her blood-test HLA haplotypes (Yu et al. 2002).因此，她可能生出血液检测中不携带她HLA单倍型的孩子（Yu等，2002）。
Similarly, a father who “failed” a paternity test from a son conceived at IVF— could this have been a laboratory mix-up?—turned out himself to be a tetragametic 46,XY//46,XY chimera.同样，一位在试管婴儿中“未通过”亲子鉴定的父亲——这可能是实验室混淆吗？——结果他自己是一个四配子46,XY//46,XY嵌合体。
The child came from sperm due to tissue deriving from the father’s absorbed fraternal co-twin, and his genetic profile was that of a nephew of his father (Baird et al. 2015).孩子来自源自父亲吸收的异卵双胞胎兄弟组织的精子，其遗传谱系相当于父亲的侄子（Baird等，2015）。
The more usual form is “confined” chimerism, in which only one tissue—that is, blood—possesses the two cell lines.更常见的形式是“局限性”嵌合体，其中仅一种组织（即血液）拥有两个细胞系。
This is due to twin-to-twin (or feto-fetal) transfusion, when dizygous twins have intimately opposed placentae, allowing vascular connections (“anastomoses”) to form between them, with marrow colonization by the other twin’s hematogenous cells.这是由于双胎间（或胎儿间）输血，当异卵双胞胎的胎盘紧密相邻时，允许血管连接（“吻合”）形成，并伴有另一双胞胎造血细胞的骨髓定植。
Sudik et al. (2001), for example, describe a woman typing XY in almost all (99%) of peripheral lymphocytes, but she was 46,XX on three other tissues, including ovarian; she had had a twin brother who had died as a neonate.例如，Sudik等（2001）描述了一名女性，其外周淋巴细胞几乎全部（99%）为XY型，但其他三种组织（包括卵巢）为46,XX；她曾有一个在新生儿期死亡的双胞胎兄弟。
Somewhat stretching the analogy, Bianchi (2000) makes the intriguing suggestion that, due to the retention and persistence of fetal blood cells following delivery, every mother is, in a sense, a hematologic (micro)chimera.稍微延伸一下这个类比，比安奇（2000）提出了一个引人入胜的观点：由于分娩后胎儿血细胞的保留和持续存在，从某种意义上说，每一位母亲都是一个血液学（微）嵌合体。
TWINNING Dizygous twinning is more frequent in mothers in their late 30s, and so it is not remarkable that occasionally twins are born, one with normal chromosomes and the other with a maternal-age-related aneuploidy.双卵双胎在35岁以上的母亲中更为常见，因此偶尔会出现双胞胎中一个染色体正常、另一个因母亲年龄相关非整倍体而异常的情况，这并不罕见。
Monozygous twinning could happen in an abnormal conception just as in a normal one, and the occasional instance of twins concordant for an abnormal karyotype is to be expected (Schlessel et al. 1990).单卵双胎可能发生在异常受孕中，如同正常受孕一样，偶尔出现双胎核型异常一致的情况也是可以预期的（Schlessel等，1990）。
Rather more remarkable is the case of monozygous (MZ) twins discordant for karyotype—clearly, 21 For the record, the chimera of classical mythology was “in the forepart a lion, in the hinder a serpent, and in the midst a goat.” Note the // descriptive format.更为引人注目的是核型不一致的同卵双胞胎案例——显然， 21 需要说明的是，古典神话中的奇美拉“前部为狮，后部为蛇，中部为羊”。注意其//描述性格式。
26 STRUCTURAL REARRANGEMENT
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Origins and Consequences of Chromosome Pathology 55 the adjective “identical” is inappropriate here!染色体病理学的起源与后果 55 形容词“相同的”在此处不恰当！
Rogers et al. (1982) studied monochorionic twin brothers, one 46,XY and the other 47,XY,+21 with Down syndrome, in whom genetic analysis supported a diagnosis of monozygosity; similarly, Chanes et al. (2021) describe MZ twins, one normal, the other with ring(13) mosaicism.Rogers等人（1982）研究了单绒毛膜双胞胎兄弟，其中一人为46,XY，另一人为47,XY,+21且患有唐氏综合征，遗传分析支持同卵双生的诊断；类似地，Chanes等人（2021）描述了同卵双生双胞胎，其中一人正常，另一人存在13号环状染色体嵌合体。
In this type of twinning, the assumption is that either a mitotic nondisjunction or a mitotic rearrangement occurred in one of the two monozygous embryos from an initially normal conception; or, vice versa, an initially 47,XY,+21 conceptus underwent splitting, with loss of a chromosome 21 then occurring in one of the newly created embryos.在这种孪生类型中，假设最初正常受孕的两个单卵胚胎之一发生了有丝分裂不分离或有丝分裂重排；或者相反，最初为47,XY,+21的受孕体发生了分裂，随后其中一个新形成的胚胎丢失了一条21号染色体。
A number of similar cases are on record,22 including monozygous twins of opposite gender (Lewi et al. 2006; Stemkens et al. 2007; Zech et al. 2008).类似病例已有不少记录，22包括异性别的单卵双胞胎（Lewi等人，2006；Stemkens等人，2007；Zech等人，2008）。
Perhaps the most extraordinary circumstance of chromosomal discordance in monozygous twins concerns the acardiac (that is, lacking a heart) fetus.也许单卵双胞胎中染色体不一致最不寻常的情况与无心（即缺少心脏）胎儿有关。
Trisomy 2 is one of the aneuploidies observed (Mihci et al. 2009).2号三体是观察到的非整倍体之一（Mihci等人，2009年）。
An initially normal conceptus might generate a trisomy 2 cell line that then separates and produces the co-twin, or an initially trisomic conceptus gives rise to a “corrected” lineage.一个最初正常的受精卵可能产生一条三体2号染色体的细胞系，随后该细胞系分离并形成共双胞胎；或者一个最初三体的受精卵产生一条“校正后”的细胞谱系。
It is only the presence of the normal twin that allows the acardiac co-twin to survive, at least temporarily, with placental vascular connections providing blood circulation (twin reverse arterial perfusion, TRAP) from normal to abnormal twin.正是由于正常双胎的存在，无心双胎才能（至少暂时）存活，胎盘血管连接为其提供了从正常双胎到异常双胎的血液循环（双胎反向动脉灌注，TRAP）。
We have seen such a case due to trisomy 3, with the affected acephalic, acardiac fetus surviving through to the second trimester, of barely recognizable human form (and see Figure 20–24).我们曾见过一例因3号染色体三体导致的无头无心畸形胎儿，该胎儿存活至孕中期，其形态几乎无法辨认为人形（见图20-24）。
STRUCTURAL REARRANGEMENT The following classical structural rearrangements may be listed: translocations, insertions, inversions, isochromosomes, duplications, deletions, rings, and complex rearrangements.结构重排 以下经典的结构重排类型可能列出：易位、插入、倒位、等臂染色体、重复、缺失、环状染色体以及复杂重排。
These may be very obvious on classical karyotyping or, for smaller deletions or duplications (3–5 Mb), may have required high-resolution banding for identification.这些在经典核型分析中可能非常明显，而对于较小的缺失或重复（3–5 Mb），则可能需要高分辨率显带才能识别。
With molecular karyotyping, imbalances of submicroscopic size, typically measured in kilobases, are detectable: these are referred to as “microdeletion” and “microduplication,” or alternatively, as “copy number variants” (CNVs).利用分子核型分析，可检测到亚显微水平的大小失衡（通常以千碱基计），这些失衡被称为“微缺失”和“微重复”，或称为“拷贝数变异”（CNVs）。
In general parlance, the terms microdeletions and microduplications are often used in a setting of assumed pathogenicity, whereas CNV may need a qualifying adjective of benign, pathogenic, or of uncertain status.在日常用语中，微缺失和微重复通常被假定为具有致病性，而拷贝数变异则可能需要加上良性、致病性或意义未明的限定形容词。
All arose de novo at one point—whether with the index case in whom the abnormality was discovered, or in a parent or more distant ancestor, with a balanced or unbalanced form transmitted thereafter in the family.所有异常最初都是新发产生的——无论是在发现该异常的索引病例中，还是在父母或更远的祖先中，随后以平衡或不平衡的形式在家族中传递。
Jacobs (1981) derived the following mutation rates for the generation of de novo classical rearrangements: 1.6 × 10–4 per gamete for the balanced reciprocal translocation, and 2.9 × 10–4 per gamete for unbalanced rearrangements.23 Concerning CNVs, the mutation rate for larger (>500 kb) microdeletions/duplications is 6.5 × 10–3 per gamete (Itsara et al. 2010).Jacobs（1981）推导出以下新生经典重排的突变率：平衡相互易位为每配子1.6 × 10⁻⁴，非平衡重排为每配子2.9 × 10⁻⁴。23 关于拷贝数变异（CNV），较大（>500 kb）微缺失/重复的突变率为每配子6.5 × 10⁻³（Itsara等，2010）。
In other words, out of 100,000 gametes, on average 16 will have a balanced and 29 an unbalanced de novo classical rearrangement, while 650 will have a de novo larger CNV. 22 It is plausible that in some instances, the presence of different cell lineages contributes to the monozygotic twinning process. 23 These conclusions were derived from data of several studies of pregnancies that were able to “survive long enough to give rise to a recognized pregnancy”: in other words, from clinical miscarriage and newborn data.换句话说，在10万个配子中，平均有16个携带平衡的、29个携带不平衡的新发经典重排，而650个携带新发较大拷贝数变异。
Jacobs acknowledges that these figures will surely be underestimates. 56 BASIC CONCEPTS Mechanisms of Formation of Structural Rearrangement The human karyotype is hostage to the fine detail of its structure.雅各布斯承认，这些数字肯定会被低估。 56 基本概念 结构重排的形成机制 人类核型受制于其结构的精细细节。
Molecular analysis of structural chromosome rearrangements and their breakpoints has shed light on the underlying generative mechanisms.染色体结构重排及其断裂点的分子分析揭示了其潜在的生成机制。
In particular, it is clear that different mutational mechanisms apply for recurrent versus non-recurrent rearrangements.特别明显的是，复发性重排与非复发性重排所涉及的突变机制不同。
Recurrent rearrangements share essentially the same size and genomic content in unrelated individuals, the breakpoints being fixed by the presence of highly homologous long flanking repeats.复发性重排在无关个体中具有基本相同的大小和基因组内容，其断裂点由高度同源的长侧翼重复序列的存在所固定。
In contrast, non-recurrent rearrangements have a size and genomic content that is unique to the individual.相比之下，非复发性重排具有个体独特的片段大小和基因组内容。
Carvalho and Lupski (2016) and Burssed et al. (2022) provide comprehensive reviews.Carvalho和Lupski（2016）以及Burssed等人（2022）提供了全面的综述。
Recurrent Rearrangements and Nonallelic Homologous Recombination The common basis for recurrent del/dup rearrangements lies in the existence of long tracts of DNA sequences, generally of some thousands of base pairs, known as segmental duplications or low copy repeats (LCRs).重复性重排与非等位同源重组 重复性缺失/重复重排的共同基础在于存在长段DNA序列，通常为数千个碱基对，称为片段重复或低拷贝重复序列（LCRs）。
These LCRs are seen throughout the genome (comprising 6.6% of the genome; Nurk et al. 2022), and are sufficiently similar (“paralogous,” rather than exactly homologous) that they enable the erroneous coming-together of different chromosome regions.这些LCRs遍布整个基因组（占基因组的6.6%；Nurk等人，2022），并且足够相似（“旁系同源”，而非完全同源），以至于它们会导致不同染色体区域的错误结合。
The two sequences involved in a particular exchange have a length of near-perfect homology, and this is the site of the actual strand exchange.特定交换中涉及的两个序列具有近乎完美的同源性长度，而此处正是实际链交换发生的位点。
In other words, “ectopic synapsis” sets the scene for a subsequent “ectopic homologous recombination.” This is referred to as nonallelic homologous recombination (NAHR; Figure 3–17), and meiosis is the usual setting.“异位联会”为随后的“异位同源重组”创造了条件。这被称为非等位同源重组（NAHR；图3–17），减数分裂是其通常发生的背景。
Non-Recurrent Rearrangements and Nonhomologous End Joining Non-recurrent structural rearrangements are characterized by the seemingly random locations of breakpoints, leading to individual del/dups of unique size and genomic content.非复发性重排与非同源末端连接 非复发性结构重排的特征是断点位置看似随机，导致产生大小和基因组内容独特的个体缺失/重复。
The absence of any long-tract sequence homology surrounding these rearrangements is indicative of nonhomologous end joining (NHEJ).这些重排周围缺乏任何长片段序列同源性，表明存在非同源末端连接（NHEJ）。
During mitotic cell division (and including in the premeiotic gametocyte), different chromosomal segments may happen to be in close proximity due to their “geographical space” within the nucleus.在有丝分裂细胞分裂过程中（包括在减数分裂前的配子母细胞中），不同的染色体片段可能因其在细胞核内的“地理空间”而恰好彼此靠近。
Then, in the simple case, if breaks occur during replication, instead of the correct ends being brought back together, the broken ends of different segments may inappropriately be ligated.那么，在简单情况下，如果复制过程中发生断裂，正确的末端未能重新连接，不同片段的断裂末端可能会被不适当地连接起来。
More complex mechanisms underlying this breakage and rejoining include fork-stalling and template-switching, and microhomology-mediated break-induced replication (Burssed et al. 2022).这种断裂和重新连接背后更复杂的机制包括叉停滞和模板转换，以及微同源介导的断裂诱导复制（Burssed 等人，2022）。
Setting in Which De Novo Rearrangement Occurs While rearrangement could, in principle, occur during either meiosis or mitosis, and in the gonad of either sex, in fact, different chromosomal forms differ in this respect.发生新发重排的背景
Most最
27 STRUCTURAL REARRANGEMENT
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Origins and Consequences of Chromosome Pathology 57 Robertsonian translocations arise in oögenesis, at a maternal meiosis (Bandyopadhyay et al. 2002).染色体病理学的起源与后果 57 罗伯逊易位发生在卵子发生过程中，即母方减数分裂期间（Bandyopadhyay 等人，2002年）。
Microdeletions/duplications can occur in both gonadal types and mostly at a meiosis, at least inasmuch as the common cases of 7q11, 15q11q13, and 22q11 may be considered to be representative (Thomas et al. 2010).微缺失/重复可发生于两种性腺类型中，且主要发生在减数分裂期间，至少就7q11、15q11q13和22q11的常见病例而言，可被视为具有代表性（Thomas等，2010）。
On the other hand, spermatogenesis is the setting for almost all de novo non-Robertsonian reciprocal rearrangements, and both meiosis and premeiotic mitoses may be the site (Höckner et al. 2012).另一方面，精子发生几乎是所有新发非罗伯逊型相互重排的背景，而减数分裂和减数分裂前有丝分裂都可能是其发生位点（Höckner 等，2012）。
Balanced, Apparently Balanced, and Functionally Unbalanced Rearrangements Structural rearrangements can be balanced, with the correct amount of genetic material in a cell, or unbalanced, with a deletion and/or duplication of genetic material.平衡性、表观平衡性与功能性不平衡重排 结构重排可以是平衡的，即细胞内遗传物质数量正确；也可以是不平衡的，即存在遗传物质的缺失和/或重复。
Arguing somewhat circularly, in the phenotypically normal person it is inferred that although such an individual’s genetic material is in a different chromosomal arrangement, it is present in the correct (balanced) amount, and functioning properly.在表型正常的人中，有点循环论证地推断，尽管此类个体的遗传物质处于不同的染色体排列中，但其数量正确（平衡）且功能正常。
It is irrelevant to the person’s health, other than his or her reproductive health.这与个人的健康无关，除非涉及他或她的生殖健康。
It may be helpful in explaining this to think of the person’s genome as a recipe book—a series of instructions for everything that is genetically determined.将一个人的基因组比作一本食谱书——即一系列由基因决定一切的指令，或许有助于解释这一点。
If an error occurs in the pagination (a translocation) and, for example, pages 17–24 are inserted between pages 36 and 37, the recipes are all Figure 3–17.如果分页出现错误（例如错位），比如第17–24页被插在第36页和第37页之间，那么所有食谱都属于图3–17。
Non-Allelic Homologous Recombination.非等位基因同源重组。
Notes: NAHR is the basis of many deletions and duplication.NAHR是许多缺失和重复的基础。
In this construction, the grey arrows represent DNA segments of 90%–98% similarity, and orange arrows of segments of >98% similarity.在此结构中，灰色箭头代表相似度为90%–98%的DNA片段，橙色箭头代表相似度>98%的片段。
Between the two >98% sequences is a segment of unique DNA (black line, asterisked).在两个>98%的序列之间是一段独特的DNA（黑线，标有星号）。
An inappropriate lining-up of a pair of very similar sequences is followed by crossing-over, at X above.一对非常相似的序列不恰当对齐后，在X处发生交叉互换。
A new hybrid “orange segment” is created from part of one and a part of the other (the two parts either side of the dotted lines), but this will have practically the same DNA sequence as it did before.一个新的杂交“橙子片段”由一部分和另一部分（虚线两侧的两个部分）组合而成，但其DNA序列实际上与之前几乎相同。
In consequence of this recombination, chromosomes are generated, one with a deletion of the segment of unique DNA, and the other with a duplication.由于这种重组，产生了染色体，一条缺失了独特DNA片段，另一条则发生了重复。
Two classic examples both reside in chromosome 17: Smith-Magenis syndrome and Potocki-Lupski syndrome are due to deletion and duplication, respectively, for the segment 17p11.2p11.2.两个经典例子都位于17号染色体上：史密斯-马格尼斯综合征和波托茨基-卢普斯基综合征分别由17p11.2p11.2片段的缺失和重复引起。
A little further up the 17 short arm, a 1.7 Mb segment within 17p12, including the PMP22 gene, is deleted in hereditary pressure-sensitive neuropathy, and duplicated in Charcot-Marie-Tooth neuropathy.在17号短臂稍上方，17p12内一段1.7 Mb的片段（包含PMP22基因）在遗传性压力敏感性神经病中缺失，而在夏科-马里-图斯神经病中重复。
Source: Drawn after CMB Carvalho and JR Lupski, Mechanisms underlying structural variant formation in genomic disorders, Nat Rev Genet 17:224–238, 2016.根据CMB Carvalho和JR Lupski在《基因组疾病中结构变异形成的机制》（Nat Rev Genet 17:224–238, 2016）一文绘制。
Courtesy JR Lupski, and with the permission of Springer Nature. 58 BASIC CONCEPTS still there; they are still perfectly capable of being read.承蒙JR Lupski惠允，并经Springer Nature许可。 58 基本概念 仍然存在；它们仍然完全能够被读取。
If a sequence of pages is inserted upside down (an inversion), one need only turn the book around to read them.如果一叠页面被倒着插入（倒位），只需将书本翻转过来即可阅读。
If a phenotypically abnormal person has a rearrangement that is balanced on classical laboratory study, one can only speak, at the cytogenetic level, of the rearrangement being “apparently balanced.” In the case of an associated cognitive impairment, one can suggest (and more so in a de novo case), but not necessarily state with certainty, that the observed phenotype may be due to the identified karyotype.如果一个表型异常的人，在经典实验室研究中具有平衡性重排，那么在细胞遗传学层面，只能称该重排为“表观平衡”。若伴有认知障碍，可以推测（在新发案例中更是如此），但未必能肯定地说，观察到的表型可能源于所识别的核型。
Modern methodologies can clarify such cases as being either indeed truly balanced, or with very subtle imbalances.现代方法可以澄清此类案例究竟是真正平衡，还是存在极其微小的不平衡。
A rearrangement that is balanced at the genomic level may yet lead to a phenotypic consequence, due to gene disruption or due to “position effect.” As an example of gene disruption, consider the well-known PMP22 gene at 17p11.2, the basis of Charcot-Marie-Tooth and pressure-sensitive neuropathy (Chapter 14).在基因组水平上平衡的重排仍可能导致表型后果，原因在于基因破坏或“位置效应”。作为基因破坏的例子，考虑位于17p11.2的著名PMP22基因，它是夏科-马里-图斯病和压力敏感性神经病的病因（第14章）。
Nadal et al. (2000) studied a mother and son, both of whom presented with pressure-sensitive neuropathy.Nadal等人（2000年）研究了一对母子，两人均表现为压力敏感性神经病。
The classical cytogenetic study showed them to be heterozygotes for the apparently balanced translocation t(16;17)(q12;p11.2).经典细胞遗传学研究表明，他们为表观平衡易位t(16;17)(q12;p11.2)的杂合子。
Applying the technology of the day, the chromosome 17 breakpoint was shown to have been sited actually within the PMP22 gene.应用当时的技术，发现17号染色体的断裂点实际上位于PMP22基因内部。
This disruption would have led to a functional haploinsufficiency, which is known to be the basis of pressure-sensitive neuropathy.这种破坏会导致功能性单倍体不足，已知这是压力敏感性神经病的基础。
Another such example is described in Dupont et al. (2013), who identified a COL2A1 disruption in a family with Stickler syndrome, the affected persons having inherited a rcp(12;15) (q13;q22.2); COL21A is located at 12q13.11.另一个类似例子见于Dupont等人（2013年）的研究，他们在一个Stickler综合征家族中发现了COL2A1基因破坏，受累者遗传了rcp(12;15)(q13;q22.2)；COL21A位于12q13.11。
Redin et al. (2017) and Lowther et al. (2022), applying molecular methodology, address the question in the study of large cohorts of translocation carriers.Redin等人（2017年）和Lowther等人（2022年）应用分子方法，在大型易位携带者队列研究中探讨了这一问题。
Comparing those with a normal (n = 304) and those with an abnormal (a developmental disorder) phenotype (n = 406) in Lowther et al., those with an abnormal phenotype had a sevenfold increased likelihood, compared to the normal group, to have the breakpoint disrupt a known developmental gene.在Lowther等人的研究中，比较表型正常组（n=304）和表型异常（发育障碍）组（n=406），与正常组相比，表型异常组断裂点破坏已知发育基因的可能性高出七倍。
As one such example, the TCF4 gene (Chapter 14; Pitt-Hopkins syndrome) at 18q21 was disrupted in some of the phenotypically abnormal cases but none of the normals.其中一个例子是位于18q21的TCF4基因（第14章；Pitt-Hopkins综合征），在一些表型异常病例中被破坏，而正常人中无一例。
Concerning position effect, one of the earliest examples is of the SOX9 gene at 17q25.1: Chromosomal rearrangement in the vicinity can result in loss of long-range regulation and hence non-expression of the (intact) gene, with sex reversal, campomelic dysplasia, and Pierre Robin syndrome possible phenotypic consequences (Gordon et al. 2014) (Figure 3–18).关于位置效应，最早的例子之一是位于17q25.1的SOX9基因：其附近的染色体重排可能导致长程调控丧失，从而使（完整的）基因不表达，可能的表型后果包括性反转、弯肢发育不良和皮埃尔·罗班综合征（Gordon等人，2014年）（图3-18）。
Sophisticated methodologies can reveal in closer detail the Figure 3–18.精密方法可以更详细地揭示图3-18。
Position Effect in an Apparently Balanced Translocation.表观平衡易位中的位置效应。
Notes: An apparently balanced translocation causing the syndrome of campomelic dysplasia (which includes skeletal, genital, and brain defects).注释：一种表观平衡易位导致弯肢发育不良综合征（包括骨骼、生殖器和脑部缺陷）。
One breakpoint is at 17q25.1, on or close to the SOX9 locus (shown as dot on the cartoon karyotype), where the basis of the syndrome lies.一个断裂点位于17q25.1，在SOX9基因座之上或附近（在卡通核型中以点表示），该综合征的病因即在于此。
One possibility is that the gene is disrupted.一种可能性是基因被破坏。
Or, an influence of adjacent chromosome 5 chromatin (“position effect”) leads to inactivation of the SOX9 gene on the der(17), the functional SOX9 haploinsufficiency then being responsible for the phenotype.或者，邻近5号染色体染色质的影响（“位置效应”）导致der(17)上的SOX9基因失活，功能性SOX9单倍体不足进而引起表型。
Source: From R Savarirayan and A Bankier, Acampomelic campomelic dysplasia with de novo 5q;17q reciprocal translocation and severe phenotype, J Med Genet, 35:597–599, 1998.来自R Savarirayan和A Bankier的研究，Acampomelic campomelic发育不良伴新发5q;17q相互易位及严重表型，J Med Genet, 35:597–599, 1998。
28 MICRODELETIONS MICRODUPLICATIONS AND COPY NUMBER VARIANTS OF INCOMPLETE PENETRAN
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Origins and Consequences of Chromosome Pathology 59 pathogenetic mechanism in some such cases, in which a region of influence—a “topologically associated domain” (TAD)—is implicated.染色体病理学的起源与后果 59 某些此类病例的致病机制涉及一个影响区域——即“拓扑关联结构域”（TAD）。
Wallis et al. (2021) studied a family with a history of lymphedema and distichiasis (LDS), segregating a rcp(16;22) (q24;q13.1), and showed that the (normal) LDS locus at 16q24.1, FOXC2, this locus lying within 16q24, had been separated from its normal control due to the translocation breakpoint being close by, 120 kb upstream.Wallis等人（2021）研究了一个有淋巴水肿和双行睫（LDS）家族史的家系，该家系携带rcp(16;22)(q24;q13.1)易位，并显示位于16q24.1的正常LDS基因座FOXC2（该基因座位于16q24内）因其上游120 kb处的易位断点而与其正常调控区域分离。
This compromise of genetic control led to the appearance of the syndrome.这种遗传调控的受损导致了该综合征的出现。
There may be no loss or gain of DNA in such cases; in other words, the rearrangement is genomically balanced, but functionally unbalanced.此类病例中可能没有DNA的丢失或获得；换言之，重排在基因组上是平衡的，但在功能上是不平衡的。
MICRODELETIONS, MICRODUPLICATIONS, AND COPY NUMBER VARIANTS OF INCOMPLETE PENETRANCE AND VARIABLE EXPRESSIVITY While the classic chromosome disorders are characterized by complete penetrance,24 the picture with the molecular-defined microdeletions/duplications is different.不完全外显率和可变表达性的微缺失、微重复及拷贝数变异 虽然经典染色体疾病以完全外显率为特征，24 但分子定义的微缺失/重复的情况则不同。
Some carriers may display no clinical abnormality, and yet a child of theirs may have presented with obvious symptomatology.某些携带者可能无任何临床异常，但其子女却可能出现明显症状。
If the “normal” parent is studied more closely, microsigns of the phenotype associated with that imbalance may be discerned; but they remain within the range of what is considered normal in the general population, and they can function as independent, productive adults.如果对“正常”父母进行更仔细的研究，可能会发现与该不平衡相关的表型的微小迹象；但这些迹象仍处于一般人群认为正常的范围内，且他们能够作为独立、有生产力的成年人生活。
These “normal” parents are considered to be nonpenetrant with respect to the imbalance in question.这些“正常”父母被认为对所讨论的不平衡具有非外显性。
It is more particularly with autism (Chapter 25) and non-dysmorphic cognitive impairment that these matters apply.这些问题尤其适用于自闭症（第25章）和非畸形认知障碍。
The basis of this variation may lie in the coexistence of different CNVs or SNP variants, most likely on another chromosome, and inherited quite coincidentally.这种变异的基础可能在于不同CNV或SNP变异的共存，这些变异很可能位于另一条染色体上，并且是偶然遗传的。
Each imbalance might not suffice to cause a phenotype on its own, but the two together may add up to abnormality.每种不平衡本身可能不足以引起表型，但两者结合可能导致异常。
This is the “two-hit” hypothesis (Girirajan et al. 2010; Atli et al. 2022).这就是“二次打击”假说（Girirajan等人，2010年；Atli等人，2022年）。
Most often, one hit (the first hit) will be the more important, and the second hit could be due to any one of a number of different “lesser” imbalances, which typically would warrant being called no more than a “VUS” (variant of uncertain significance).25 It might be more accurate to speak of two or more hits multiplying together, rather than adding up, to produce a phenotype of combined effect.大多数情况下，一次打击（第一次打击）更为重要，而第二次打击可能由多种不同的“较轻”不平衡中的任何一种引起，这些不平衡通常仅被称为“VUS”（意义未明变异）。25 更准确的说法可能是两次或多次打击相乘而非相加，以产生联合效应的表型。
Multiple hits contribute to a “liability threshold” beyond which a phenotype emerges (Pizzo et al. 2019; Jensen et al. 2021; Smolen et al. 2023).多次打击共同促成“易感性阈值”，超过该阈值则出现表型（Pizzo等人，2019年；Jensen等人，2021年；Smolen等人，2023年）。
This concept is illustrated in study of the well-known 16p12.1 deletion (Figure 3–19).这一概念在著名的16p12.1缺失研究中得到了说明（图3–19）。
These further hits comprise CNVs, rare sequence variants of variable impact, or the combined effect of multiple common variants (in other words, polygenic inheritance).这些进一步的打击包括CNV、影响程度不同的罕见序列变异，或多个常见变异的联合效应（即多基因遗传）。
Rosenfeld et al. (2013) reviewed a number of the more common microdeletions/ duplications (“first-hit” imbalances), establishing penetrance estimates ranging from 10% to 62% (the 62% referring to the 16p11.2 microdeletion just mentioned).Rosenfeld等人（2013年）回顾了若干较常见的微缺失/重复（“首次打击”不平衡），得出外显率估计值范围为10%至62%（其中62%指的是刚才提到的16p11.2微缺失）。
Their 24 Penetrance is a quantitative descriptor and refers to the percentage fraction of a particular genetic cohort who show phenotypic abnormality.他们的 24 外显率是一个定量描述符，指特定遗传群体中显示表型异常的百分比。
In such a population, in which the fraction is less than 100%, we may speak of incomplete penetrance; in a single individual showing no abnormality, this is nonpenetrance.在这样一个比例低于100%的群体中，我们可以说是不完全外显率；而在一个无异常表现的个体中，这称为非外显性。
Expressivity is qualitative, and reflects the range of clinical manifestation in those in whom a condition has been penetrant.表现度是定性的，反映了在已表现出外显性的个体中，临床表现的多样性范围。
It may sometimes become a matter of semantics whether a subtly abnormal person is considered to represent nonpenetrance, or penetrance with very mild expressivity. 25 A rare and different form of two-hit mechanism concerns the “unmasking” of a recessive allele on a normal homolog, due to a deletion of that segment on the other chromosome (Poot 2012; Paciorkowski et al. 2013).有时，一个轻微异常的人是否被视为代表不完全外显，或具有极轻微表现度的外显，可能成为一个语义问题。
29 EPIGENETICS AND GENOMIC IMPRINTING
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60 BASIC CONCEPTS work was since followed up by others (Coe et al. 2014; Kendall et al. 2019; Redaelli et al. 2019), and culminating in the review of Goh et al. (2025) as listed in Appendix C.60 基本概念 该工作随后被其他人跟进（Coe等人，2014；Kendall等人，2019；Redaelli等人，2019），并最终在附录C所列的Goh等人（2025）的综述中达到顶峰。
EPIGENETICS AND GENOMIC IMPRINTING A formal definition of an epigenetic effect includes these points: The DNA sequence of a particular gene remains unaltered, but the capacity of this gene to be expressed is altered.表观遗传学与基因组印记 表观遗传效应的正式定义包括以下几点：特定基因的DNA序列保持不变，但该基因的表达能力发生改变。
The expression “genomic imprinting” is applied in the setting of epigenetic effects that are imposed during germline transmission.“基因组印记”这一表述应用于在种系传递过程中施加的表观遗传效应的背景下。
Some parts of some chromosomes are subject to genomic imprinting as a normal occurrence, and this imprinting is parent-specific; that is, genes in the chromosomal segment are expressed, or not expressed, according to whether the chromosome had been transmitted in the sperm or in the ovum (“parent-of-origin effect”).一些染色体的某些部分在正常情况下会受到基因组印记的影响，这种印记具有亲本特异性；也就是说，染色体片段中的基因会根据该染色体是通过精子还是卵子传递（即“亲本起源效应”）而表达或不表达。
An imprinted segment takes up an “epigenetic mark,” and the gene or genes in this segment are not expressed, leaving it to the corresponding locus or loci on the homologous chromosome from the other parent to be the only source of expression.印记片段带有一个“表观遗传标记”，该片段中的一个或多个基因不表达，使得来自另一亲本的同源染色体上的对应位点成为唯一的表达来源。
When the phenomenon was first appreciated in humans, it was naturally suspected that many forms of congenital abnormality might be due to aberrant imprinting.当这一现象首次在人类中被认识到时，人们自然怀疑许多先天性异常可能源于异常的印记。
As it has transpired, however, the practical application of genomic imprinting appears to be confined to a rather small number of cytogenetic conditions (Chapter 19).然而，事实证明，基因组印记的实际应用似乎仅限于少数细胞遗传学疾病（第19章）。
Nevertheless, the theoretical interest is considerable.尽管如此，其理论意义仍相当重大。
Most of the autosomal genome is not subject to imprinting, and it is functionally disomic.常染色体基因组的大部分不受印记影响，且在功能上是二倍体。
That is, with each locus having a pair of alleles, each of the pair is functionally active, contributing more or less equally to the genetic output from that locus.26 This is biallelic gene expression.每个基因座有一对等位基因，这对等位基因中的每一个在功能上都是活跃的，对该基因座的遗传输出贡献大致相等。26 这就是双等位基因表达。
A minority of the genome is subject to imprinting and requires only one of the pair of alleles to be active, while the other one becomes inactivated 26 But exceptions exist, and approximately 5% of autosomal genes are randomly expressed from only one or other parental allele (Gimelbrant et al. 2007).基因组中的少数区域受到印记调控，仅需要一对等位基因中的一个保持活性，而另一个则被失活。
Figure 3–19.图3–19。
The 16p12.1 Deletion in a Proband, and in the Carrier and Non-Carrier Parent.先证者中的16p12.1缺失，以及携带者和非携带者父母中的情况。
Notes: The thresholds are shown for developmental and psychiatric manifestation, according to an individual’s genetic load: the presence of the 16p deletion; the carriage of second-hit variants; and the load otherwise of variants relating to an autism polygenic risk score.阈值根据个体的遗传负荷显示发育和精神表现：存在16p缺失；携带二次打击变异；以及与自闭症多基因风险评分相关的其他变异负荷。
The deletion is carried by the proband and the carrier parent.缺失由先证者和携带者父母携带。
Some carrier parents may manifest a relatively mild psychiatric phenotype.一些携带者父母可能表现出相对轻微的精神病表型。
The non-carrier parent may have a number of different rare variants (blue), which of themselves, in this setting, are harmless, along with a variable polygenic load.非携带者父母可能携带多种不同的罕见变异（蓝色），这些变异在此情境下本身无害，同时伴随可变的多基因负荷。
But the combination, then, in the child, of the 16p deletion, along with a number of rare second-hit variants (yellow), combined with a polygenic load (polygenic risk score, blue), combine to cross a threshold sufficient to convey a developmental phenotype.然而，在子代中，16p缺失与多种罕见二次打击变异（黄色）相结合，再加上多基因负荷（多基因风险评分，蓝色），共同跨越了足以传递发育表型的阈值。
30 CONSEQUENCES OF GENETIC ABNORMALITY
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Origins and Consequences of Chromosome Pathology 61 (“silent”); in other words, the locus is functionally monosomic, with a genetic output from only one allele.染色体病理学的起源与后果 61（“沉默”）；换言之，该位点在功能上是单倍体，仅有一个等位基因产生遗传输出。
This is monoallelic expression.这就是单等位基因表达。
If the allele of maternal origin is inactivated, only the allele of paternal origin is functionally active, and vice versa.如果母源等位基因被失活，则只有父源等位基因在功能上活跃，反之亦然。
Following conception, the imprint remains through cycles of post-conceptional somatic mitoses: The chromosome “remembers” the sex of the parent who contributed it (put differently, it retains its epigenetic mark).受孕后，印记通过受孕后体细胞有丝分裂周期得以保留：染色体“记住”了提供它的亲本性别（换句话说，它保留了其表观遗传标记）。
The imprinting pattern may be specific to a certain tissue or to a certain developmental stage (Ideraabdullah et al. 2008).印记模式可能特定于某种组织或某个发育阶段（Ideraabdullah 等，2008）。
Thus, in some tissues a gene may express monoallelically, whereas in other tissues biallelic expression is retained; or a gene may express monoallelically in a specific tissue at one stage in embryogenesis, and biallelically thereafter.因此，在某些组织中，基因可能表现为单等位基因表达，而在其他组织中则保留双等位基因表达；或者，基因在胚胎发生的某个阶段于特定组织中单等位表达，此后转为双等位表达。
X chromosome inactivation is a special case.X染色体失活是一个特例。
Parent-of-origin imprinting is a normal mechanism of gene regulation.亲本起源印记是一种正常的基因调控机制。
It is mediated through a process taking place during gametogenesis, of which the physical basis includes methylation of cytosine bases within the gene(s) or in controlling sequences upstream of it.它通过配子发生过程中的一个过程介导，其物理基础包括基因内或上游控制序列中胞嘧啶碱基的甲基化。
This process is reversible, and in the “life” of an autosomal allele or chromosomal segment, as it passes from individual to individual down the generations and across the centuries, imprinting—the epigenetic mark—will be acquired, maintained, lost (“erased”), reacquired (“reset”), and lost again, according to the sexes of the individuals through whom it is transmitted.这一过程是可逆的，在常染色体等位基因或染色体片段的“生命周期”中，当它代代相传、跨越世纪时，印记——表观遗传标记——会根据传递它的个体性别而被获得、维持、丢失（“擦除”）、重新获得（“重置”）并再次丢失。
Throughout, it retains the same DNA sequence.在此过程中，它始终保留相同的DNA序列。
Mechanisms Whereby Functional Genetic Abnormality Can Arise In the context of imprinting, we may consider three categories of functional genetic defect.功能性遗传异常产生的机制 在印记的背景下，我们可以考虑三类功能性遗传缺陷。
These are as follows: uniparental disomy with overexpression or non-expression of genes in certain chromosomal segments; deletion with non-expression; and relaxation of imprinting with overexpression.具体如下：单亲二体导致某些染色体片段中基因的过度表达或不表达；缺失导致不表达；印记松弛导致过度表达。
Uniparental disomy will lead to either biallelic expression, or to no expression, at the locus or loci within the imprintable segment.单亲二体将导致可印记片段内一个或多个位点出现双等位基因表达或无表达。
If a deletion removes a chromosomal segment that would otherwise have been “silenced,” all that is lost is a nonfunctioning genetic segment, and there is no untoward consequence.如果缺失移除了一段本应被“沉默”的染色体片段，那么丢失的只是一个无功能的遗传片段，不会产生不良后果。
On the other hand, if the deletion removes the segment on the active chromosome, the corresponding part of the other homolog is inactive, and so neither chromosome will be genetically functioning in this segment; in a sense, the silent allele is unmasked.另一方面，如果缺失发生在活性染色体上的片段，则另一同源染色体对应部分处于失活状态，因此两条染色体在该片段均无遗传功能；从某种意义上说，沉默等位基因被暴露出来。
Relaxation of imprinting allows a segment that should be non-expressed to lose its imprint.印记松弛使得本应不表达的片段失去其印记。
The locus or loci contained therein will be operating biallelically, which will be, theoretically, at double normal capacity.其中所含的一个或多个基因座将以双等位基因方式运作，理论上其功能将达到正常水平的两倍。
These mechanisms are dealt with in detail in Chapter 19.这些机制将在第19章中详细讨论。
CONSEQUENCES OF GENETIC ABNORMALITY Structural Imbalance Our physical anatomy is due to our chromosomes (Gardner 2016; Anastasiadou et al. 2024).遗传异常的结果 结构失衡 我们的身体结构由染色体决定（Gardner 2016; Anastasiadou et al. 2024）。
Chromosome imbalances are harmful because of the fundamental reason that many genes are dosage-sensitive.染色体失衡之所以有害，根本原因在于许多基因具有剂量敏感性。
And if megabase amounts of chromatin are involved, it is highly likely dosage-sensitive genes will be included in the imbalanced segment(s).如果涉及兆碱基级别的染色质，那么剂量敏感基因很可能包含在失衡片段中。
In duplications, there is 150% of the normal amount of this chromosomal segment, 62 BASIC CONCEPTS and in the deletion there is 50% of the normal amount.在重复的情况下，该染色体片段的正常含量为150%，而在缺失的情况下则为正常含量的50%。
The imbalance involves a whole chromosome (full aneuploidy) or a part of a chromosome.失衡涉及整条染色体（完全非整倍体）或染色体的一部分。
From classical cytogenetics, the latter state is described as partial or segmental aneuploidy, a deletion or a duplication.根据经典细胞遗传学，后一种情况被称为部分或节段性非整倍体，即缺失或重复。
In molecular karyotyping, in which the focus is on much smaller segments, the terms used are microdeletion and microduplication, or CNV deletion or duplication.在分子核型分析中，由于关注的是更小的片段，使用的术语是微缺失和微重复，或CNV缺失或重复。
An incorrect amount of dosage-sensitive genetic material in every cell of the conceptus distorts its development to a greater or lesser extent.胚胎每个细胞中剂量敏感遗传物质的错误数量会不同程度地扭曲其发育。
As discussed above, large losses or gains almost invariably set early anatomical development so awry that natural abortion occurs.如上所述，大范围的缺失或增加几乎总是使早期解剖发育严重偏离，导致自然流产。
Lesser imbalances may be compatible with continued intrauterine survival, but with the eventual production of a phenotypically abnormal child.较轻的失衡可能允许胎儿在子宫内继续存活，但最终会产下表型异常的孩子。
Very minor partial aneuploidies may cause defects that are not readily detectable in early infancy; and some chromosomal “defects” may be without phenotypic effect.非常轻微的部分非整倍体可能导致婴儿早期不易察觉的缺陷；而某些染色体“缺陷”可能没有表型效应。
However, as a first principle, anything but 100% of the normal amount of genetic material (in classical, megabase cytogenetic terms) produces a less than 100% normal phenotype.然而，作为首要原则，任何偏离正常遗传物质100%含量（以经典兆碱基细胞遗传学术语衡量）的情况，都会产生低于100%正常表型的结果。
Cognitive impairment is the almost universal consequence of classical autosomal imbalance, while much intellectual disability is due to a chromosome abnormality.认知障碍是经典常染色体失衡几乎普遍的结果，而许多智力残疾正是由染色体异常引起的。
On the other hand, imbalances detectable only by molecular karyotyping (CNV del/ dups) may be so small that no dosage-sensitive material is affected, and the phenotype is unaffected; or, the imbalance may only lead to phenotypic abnormality when it exists in the company of another micro-imbalance elsewhere in the genome (“second-hit” effect, as discussed above).另一方面，仅通过分子核型分析（CNV缺失/重复）才能检测到的失衡可能非常微小，以至于未影响任何剂量敏感物质，表型不受影响；或者，这种失衡只有在与基因组其他位置的另一个微失衡共存时（即上文讨论的“二次打击”效应）才会导致表型异常。
The distinction between very small classical and larger molecular imbalances is not as clear-cut as the foregoing might suggest, and indeed some cases could carry either description; but it is useful nevertheless to consider these as two categories.非常小的经典失衡与较大的分子失衡之间的区别并不像上述内容所暗示的那样明确，实际上某些病例可能同时符合两种描述；但将其视为两个类别仍然是有用的。
It is generally too simplistic to think of deletions and duplications leading to opposite qualities of phenotype (Neri and Romana Di Raimo 2010).通常认为缺失和重复会导致相反的表型质量过于简单化（Neri and Romana Di Raimo 2010）。
But in some instances the concept of “type and countertype,” originally proposed by Lejeune (1966), may be invoked.但在某些情况下，可以引用最初由Lejeune（1966）提出的“类型与反类型”概念。
Deletion of 7p15 may cause the cranial bones to fuse prematurely (craniosynostosis) due to abnormal behavior of osteoblasts at their periphery, whereas duplication leads to underdevelopment of the skull, with a large and confluent fontanelle (Stankiewicz et al. 2001) (Figure 14–31).7p15的缺失可能导致颅骨过早融合（颅缝早闭），原因是其边缘的成骨细胞行为异常；而重复则导致颅骨发育不全，出现大而融合的前囟（Stankiewicz et al. 2001）（图14-31）。
Deletion of 15q26.1qter (which removes the growth factor locus IGFR1) is associated with intrauterine growth retardation, whereas dup(15)(q26.1qter) may cause a syndrome of post-natal overgrowth (Faivre et al. 2002; Nagai et al. 2002).15q26.1qter缺失（去除生长因子位点IGFR1）与宫内生长迟缓相关，而dup(15)(q26.1qter)可能导致出生后过度生长综合征（Faivre等，2002；Nagai等，2002）。
Similarly, carriers of reciprocal CNVs at 16p11.2 exhibit mirror phenotypes of obesity/macrocephaly (deletion) and underweight/microcephaly (duplication) (Loviglio et al. 2017).类似地，16p11.2相互拷贝数变异携带者表现出肥胖/巨头畸形（缺失）和体重不足/小头畸形（重复）的镜像表型（Loviglio等，2017）。
Assessment of Imbalance With respect to classical degrees of cytogenetic imbalance, the blunt quantitative tool of haploid autosomal length (HAL; see Appendix A) measurement can be applied, although this may now be of somewhat historic interest in the molecular era.关于不平衡的评估，针对经典细胞遗传学不平衡程度，可应用单倍体常染色体长度（HAL；见附录A）这一粗略定量工具，尽管在分子时代这可能仅具有历史意义。
The largest chromosome, no. 1, comprises 8.66% of the HAL, whereas chromosome 21, the smallest, is 1.77% (Table A–1).最大的1号染色体占HAL的8.66%，而最小的21号染色体占1.77%（表A-1）。
As a very general rule, if the imbalance consists of less than 1% of HAL (corresponding to ~30 Mb), the conceptus is often viable in utero, and live birth frequently results.作为一般规律，若不平衡小于HAL的1%（约30 Mb），胚胎常在宫内可存活，并常导致活产。
If the excess is greater than 2%, in utero lethality, with spontaneous若过量大于2%，则可能导致宫内致死，并伴随自然
31 CONSEQUENCES OF GENETIC ABNORMALITY
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Origins and Consequences of Chromosome Pathology 63 abortion, is likely.染色体病理学的起源与后果 63 流产。
Imbalance involving autosomal deficiency (partial monosomy) is generally much less survivable than is duplication (partial trisomy).涉及常染色体缺失（部分单体）的不平衡通常比重复（部分三体）的存活率低得多。
A qualitative assessment is more to the point: chromosomal segments vary considerably in respect of their genetic content.定性评估更为关键：染色体片段在遗传内容上差异显著。
Insight is gained on the empiric observations of phenotypes.从表型的经验观察中可获得洞见。
Some large segments (e.g., 9p, all of 21) appear to have a substantial pre- and post-natal survivability in the trisomic state, whereas a lesser number of segments (e.g., distal 4p) are often viable when monosomic.一些大片段（如9p、整个21号染色体）在三体状态下具有显著的产前和产后存活能力，而较少片段（如远端4p）在单体状态下常可存活。
Chromosome 13 provides the most impressive examples of viability for a large autosomal imbalance.13号染色体为大型常染色体不平衡的存活能力提供了最显著的例子。
Trisomy for the whole of chromosome 13—fully 3.7% of the HAL—frequently goes through to live birth, and in the 13q– deletion syndrome, monosomy occurs for up to 2.5% of HAL.整个13号染色体的三体——占HAL的3.7%——常可活产，而在13q-缺失综合征中，单体可达HAL的2.5%。
This reflects the low gene density on this chromosome, only 6.5 genes per Mb (Table 1–1).这反映了该染色体基因密度低，仅每Mb 6.5个基因（表1-1）。
The same principle applies to chromosomes 18 and 21.27 On the other hand, chromosome 19, although small, carries a high concentration of genes, indeed the highest per length (Figure 1–4), and segmental imbalances are thus rarely viable.同一原则适用于18号和21号染色体。另一方面，19号染色体虽小，但携带高浓度基因，实际上每长度基因密度最高（图1-4），因此片段不平衡极少存活。
Occasionally, imbalance detectable classically is so “small” that the effect on the child’s physical phenotype is only very minor, and intellectual function can remain within the normal range, albeit toward the lower end of that range.偶尔，经典方法可检测的不平衡如此“微小”，以至于对儿童身体表型的影响非常轻微，智力功能可保持在正常范围内，尽管偏向该范围的下限。
Indeed, there are some segments of Mb size which, when duplicated or deleted, appear to cause no abnormality at all (Stumm et al. 2002; Barber 2005; Atli et al. 2022).事实上，有些Mb大小的片段在重复或缺失时似乎完全不引起异常（Stumm等，2002；Barber 2005；Atli等，2022）。
The concept of heritable “euchromatic deletions and duplications without phenotypic effect” is discussed in Chapter 17.可遗传的“无表型效应的常染色质缺失和重复”概念将在第17章讨论。
Molecular karyotyping has enabled a finer view of the genome, and microdeletions and microduplications of kilobase size are routinely detectable.分子核型分析使人们能更精细地观察基因组，千碱基大小的微缺失和微重复可常规检测。
These imbalances may impose a phenotype in which cognitive and behavioral abnormality is the predominant observation.这些不平衡可能引起以认知和行为异常为主要观察结果的表型。
Dysmorphism may be evident, but can be of quite minor degree.形态异常可能明显，但程度可能相当轻微。
This may reflect that these small imbalances affect only a few or even a single gene, or regulatory factor.这可能反映这些微小失衡仅影响少数甚至单个基因或调控因子。
Since the organ commanding the largest component of a person’s genome is the brain, it is plausible to suppose that “brain genes” will be the most likely type of gene to reside within the microdeletions/duplications concerned.由于控制人类基因组最大组成部分的器官是大脑，因此可以合理推测“脑基因”最可能位于相关的微缺失/微重复区域内。
Differing lengths of deleted or duplicated segments enable a dissection of the specific segmental contributions to components of an abnormal phenotype.缺失或重复片段的不同长度使得能够剖析特定片段对异常表型各组成部分的贡献。
A broad-brush “malformation map” can be produced from documenting the association of certain congenital defects or known syndromes with particular segmental aneusomies (Brewer et al. 1998, 1999; Carey and Viskochil 2007) (Figure 3–20).通过记录某些先天性缺陷或已知综合征与特定节段非整倍体的关联，可以绘制出粗略的“畸形图谱”（Brewer et al. 1998, 1999; Carey and Viskochil 2007）（图3–20）。
Specific malformations can be interrogated: van Karnebeek and Hennekam (1999) document imbalances associated with congenital heart disease, as do Thorsson et al. (2015); Tyshchenko et al. (2009) have assembled a (very preliminary) brain list; Marcelis et al. (2011) record chromosomal segments associated with anorectal malformations; and we have undertaken phenotype mapping studies with respect to epilepsy (Singh et al. 2002a) and to kidney defects (Amor et al. 2003).可针对特定畸形进行探究：van Karnebeek 和 Hennekam（1999）记录了与先天性心脏病相关的失衡，Thorsson 等人（2015）亦有相关研究；Tyshchenko 等人（2009）汇编了一份（非常初步的）脑部列表；Marcelis 等人（2011）记录了与肛门直肠畸形相关的染色体片段；我们针对癫痫（Singh et al. 2002a）和肾脏缺陷（Amor et al. 2003）进行了表型图谱研究。
Catelani et al. (2009) have searched for molecular imbalances in children with syndromic deafness.Catelani 等人（2009）在患有综合征性耳聋的儿童中搜索了分子失衡。
The chromosome regions thus illuminated may serve as candidate regions for the discovery of culprit genes.由此揭示的染色体区域可作为发现致病基因的候选区域。
Note that a one-to-one connection between a deleted/duplicated segment and a specific trait cannot necessarily be drawn; and, for example, we have proposed that the particular nervous system malformation of periventricular 27 Chromosome 21 has a similar density, at 6.7 genes/Mb, whereas chromosome 18 is the least dense, at 4.3 genes/Mb (Nusbaum et al. 2005).注意，缺失/重复片段与特定性状之间不一定存在一一对应关系；例如，我们曾提出特定神经系统畸形——脑室周围 27 号染色体具有相似密度，为 6.7 个基因/Mb，而 18 号染色体密度最低，为 4.3 个基因/Mb（Nusbaum et al. 2005）。
Figure 3–20.图3–20。
A duplication-malformation correlation map.重复-畸形关联图谱。
Some chromosomal regions, in the duplicated state, are particularly associated with certain types of malformation.某些染色体区域在重复状态下特别与特定类型的畸形相关。
Presumably, these regions harbor genes that have roles in the formation of these particular organs.推测这些区域含有在特定器官形成中起作用的基因。
Other regions (including all of chromosome 19) are unrepresented, and some of these may contain “triplo-lethal genes.” ACC, agenesis of the corpus callosum; ASD, atrial septal defect; AVSD, atrioventricular septal defect; PDA, patent ductus arteriosus; VSD, ventricular septal defect.其他区域（包括整个19号染色体）未被呈现，其中一些可能含有“三倍致死基因”。ACC，胼胝体发育不全；ASD，房间隔缺损；AVSD，房室间隔缺损；PDA，动脉导管未闭；VSD，室间隔缺损。
A similar map has been drawn for deletions (Brewer et al. 1998).已为缺失绘制了类似的图谱（Brewer et al. 1998）。
In a somewhat similar vein, autism-susceptible copy number variant loci have been mapped (Figure 25–2).以类似的方式，自闭症易感拷贝数变异位点已被定位（图25–2）。
Source: From Brewer et al. (1999), A chromosomal duplication map of malformations: Regions of suspected haplo- and triplo-lethality—and tolerance of segmental aneuploidy—in humans, Am J Hum Genet 64: 1702– 1708.来源：摘自 Brewer 等人（1999），《人类畸形染色体重复图谱：疑似单倍体和三倍体致死性区域及节段非整倍体耐受性》，Am J Hum Genet 64: 1702–1708。
Courtesy C Brewer and DR FitzPatrick, and with the permission of the University of Chicago Press.承蒙 C Brewer 和 DR FitzPatrick 提供，并获芝加哥大学出版社许可。
32 CONSEQUENCES OF GENETIC ABNORMALITY
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Origins and Consequences of Chromosome Pathology 65 nodular heterotopia might be an epiphenomenon accompanying a number of microdeletion syndromes, rather than the direct consequence of specific segmental imbalances (van Kogelenberg et al. 2010).染色体病理学的起源与后果 65 结节性异位可能是伴随多种微缺失综合征的附带现象，而非特定节段失衡的直接后果（van Kogelenberg 等，2010）。
Looking at segments as a whole is, as mentioned, to take a broad-brush approach.整体审视各个部分，如前所述，是一种宏观把握的方法。
But bear in mind that an aneuploid segment of interest is of course a length of DNA, typically containing a number of protein-coding genes, possibly as few as one, or indeed perhaps none; in the latter case, non-coding DNA may contain regulatory elements that influence activity of genes elsewhere.但需要注意的是，感兴趣的异倍体片段当然是一段DNA，通常包含若干蛋白质编码基因，可能少至一个，甚至可能一个也没有；在后一种情况下，非编码DNA可能包含影响其他位置基因活性的调控元件。
In those segments in which a single major locus is involved, such as the PMP22 gene of Charcot-Marie-Tooth disease, a (relatively) simple one-to-one genotype-phenotype relationship may apply, and the other loci resident within the segment, not being dosage-sensitive, are non-contributory.在涉及单个主要基因座的片段中，例如夏科-马里-图斯病的PMP22基因，可能适用（相对）简单的一对一基因型-表型关系，而该片段内的其他基因座由于不具有剂量敏感性，因此不起作用。
Many imbalances, however, involve a number of pheno-contributory loci; or in other words, a number of loci within the segment may be dosage-sensitive.然而，许多不平衡涉及多个表型贡献位点；换言之，该区段内的多个位点可能具有剂量敏感性。
Many authors have collected particular cases from their own experience and from the literature.许多作者从自身经验和文献中收集了特定案例。
As the data from cohorts of cases are brought together, we may be able to tease out the individual genes or regulatory elements responsible for the different components of an abnormal phenotype.随着来自不同病例队列的数据汇集起来，我们或许能够梳理出导致异常表型不同组成部分的单个基因或调控元件。
As an example of a multigene pathogenesis, Engels et al. (2012) studied five patients with molecular-defined deletions at 14q32.3, refining the phenotype map, and they hone down to a region containing just seven known genes that may be assumed, in total, to produce the phenotype as defined by them.作为多基因致病机制的一个例子，Engels等人（2012）研究了五名在14q32.3位点存在分子定义缺失的患者，细化了表型图谱，并将范围缩小至一个仅包含七个已知基因的区域，这些基因总体上可能被认为产生了他们所定义的表型。
A number of individual gene-level resources are now available to assess the pathogenicity of a given deletion or duplication based on its genetic content, including gene constraint metrics and dosage-sensitivity scores (Chapter 18).目前已有多种个体基因层面的资源可用于评估特定缺失或重复的致病性，这些资源基于其遗传内容，包括基因约束指标和剂量敏感性评分（第18章）。
The concept of genes acting “in total,” or perhaps better said “in concert,” is addressed by Carvalho et al. (2014) in their review of the 17p13 deletion (Chapter 14).Carvalho等人（2014）在其关于17p13缺失的综述（第14章）中探讨了基因“整体”作用，或者更准确地说“协同”作用的概念。
They studied the small number of genes within this segment and judged the relative roles of these genes in determining one particular aspect of the phenotype of this syndrome (microcephaly); they propose there to be functional interconnections (that is, epistasis) between some of these genes (Figure 3–21).他们研究了该片段内少数基因，并判断了这些基因在决定该综合征某一特定表型（小头畸形）中的相对作用；他们提出这些基因之间存在功能上的相互联系（即上位效应）（图3-21）。
The end result of this interaction may be a “second-level” or higher-level effect upon the phenotype; in other words, the whole may be different from the sum of the individual parts (and see also Figure 3–19).这种互动的最终结果可能对表型产生“二级”或更高级别的影响；换言之，整体可能不同于各个部分的总和（另见图3-19）。
Surely, similar scenarios apply rather widely in the generality of the chromosomal syndromes.当然，类似的情况在染色体综合征的普遍范围内相当广泛地适用。
For the most part, the clinical states due to chromosomal imbalance are fixed and static.在大多数情况下，由染色体失衡引起的临床状态是固定且静止的。
Structural defects such as a cardiac septal defect, or facial dysmorphism, are not progressive (although they may be evolving) conditions: They were established during embryogenesis and fetal development, and in essence, and unless surgically repaired, will stay that way.结构性缺陷如心脏间隔缺损或面部畸形，并非进行性疾病（尽管可能处于演变中）：它们是在胚胎发生和胎儿发育过程中形成的，本质上，除非通过手术修复，否则将保持原状。
They may, of course, set the stage for consequential progressive change, such as a urinary tract defect that has back-pressure effects upon a kidney, affecting renal function; but this is a secondary factor.当然，它们可能为后续的渐进性变化奠定基础，例如泌尿系统缺陷对肾脏产生反压效应，进而影响肾功能；但这属于次要因素。
The brain, the most vulnerable organ, is similarly fixed in terms of its underlying anatomy, and chromosome disorders would not, as a general rule, be described as neurodegenerative.大脑，这个最脆弱的器官，其基本解剖结构同样固定不变，而染色体疾病通常不会被描述为神经退行性疾病。
The most notable exception to that rule is the long-recognized dementia that typically commences around age 40 years in Down syndrome, and which reflects the effects of a triple dose of the amyloid precursor protein gene on chromosome 21, with a gradual accumulation in the brain of the abnormal protein.对此规则最显著的例外是唐氏综合征中通常在40岁左右开始的长期公认的痴呆，这反映了21号染色体上淀粉样前体蛋白基因的三倍剂量效应，导致异常蛋白在大脑中逐渐积累。
It is an obvious point, but worth restating: The defect in these aneuploid states involves too much or too little of what is normal chromosome material.这是一个显而易见的观点，但值得重申：这些非整倍体状态的缺陷涉及正常染色体物质的过多或过少。
The “third”“第三条”
33 THE SEX CHROMOSOMES
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66 BASIC CONCEPTS chromosome in standard trisomy 21 is a perfectly normal chromosome 21, with a perfectly normal complement of chromosome 21 genes.66 基本概念染色体在标准21三体中是完全正常的21号染色体，带有完全正常的21号染色体基因补体。
How, therefore, could it be that an additional amount of normal genetic message leads to an abnormal interpretation of that message?那么，额外的正常遗传信息如何导致对该信息的异常解读？
How is the “dosage effect” mediated?“剂量效应”是如何介导的？
This is one of the great remaining unanswered questions of biology (Liu et al. 2023), which we touch upon (no more than that) in Chapter 13.这是生物学中尚未解答的重大问题之一（Liu等人，2023），我们在第13章中仅略作提及（仅此而已）。
THE SEX CHROMOSOMES Sex chromosome imbalances need to be considered separately.性染色体性染色体失衡需要单独考虑。
Any X chromosomes in excess of one are, almost entirely, genetically inactivated.任何多余的X染色体几乎完全在遗传上被失活。
Thus, indicating the inactivated X in lowercase, normal females are 46,Xx; normal males are 46,XY; Turner females are 45,X; Klinefelter males are 47,XxY; and other X aneuploidies are 47,Xxx, 48,Xxxx, 48,XxYY, 49,XxxxY, and 49,Xxxxx.因此，用小写字母表示失活的X，正常女性为46,Xx；正常男性为46,XY；特纳女性为45,X；克氏男性为47,XxY；其他X非整倍体为47,Xxx、48,Xxxx、48,XxYY、49,XxxxY和49,Xxxxx。
As for the Y chromosome, its active genetic material is confined to only a small segment, these genes being mostly related to sex determination and testicular function.至于Y染色体，其活跃遗传物质仅限于一个小片段，这些基因大多与性别决定和睾丸功能相关。
Thus, despite the presence of one or more whole X or Y chromosomes in excess in the 47-, 48-, and 49-chromosome states, in utero survival remains possible.因此，尽管在47、48和49条染色体的状态下存在一条或多条多余的完整X或Y染色体，子宫内存活仍有可能。
Indeed, for 47,XXX, 47,XXY, and 47,XYY, survival from conception is apparently uncompromised.事实上，对于47,XXX、47,XXY和47,XYY，从受孕开始的存活率显然未受影响。
Gonadal development in X aneuploid males is particularly affected, and intellectual function is jeopardized to a mild or moderate or severe extent in the n ≥ 47 states in both sexes.X非整倍体男性的性腺发育尤其受影响，而在n ≥ 47的状态下，两性的智力功能均受到轻度、中度或重度损害。
The cognitive compromise may reflect, inter alia, an influence upon normal Figure 3–21.认知损伤可能尤其反映了对正常图3–21的影响。
Interaction Between Genes Influencing the Phenotype: The Interactome.影响表型的基因间相互作用：相互作用组。
The17p13 deletion syndrome: effect of individual loci upon head size, and interaction of genes within this region.17p13缺失综合征：单个位点对头围的影响，以及该区域内基因的相互作用。
Above, gene map with nine loci within the deletion segment depicted.上方，显示了缺失片段内九个位点的基因图谱。
Cross-hatched locus, severe impact upon phenotype (microcephaly); dotted locus, moderate effect upon phenotype; open locus, no apparent effect.交叉阴影位点，对表型有严重影响（小头畸形）；点状位点，对表型有中度影响；开放位点，无明显影响。
Below, proposed interaction between some of these loci, as inferred from zebrafish study.下方，根据斑马鱼研究推断出的其中一些位点之间的相互作用。
Source: From Carvalho et al., Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes, Am J Hum Genet 95:565–578, 2014.来源：摘自Carvalho等人，17p13.1片段剂量变化因多个基因的复杂遗传相互作用导致智力残疾和小头畸形，《美国人类遗传学杂志》95:565–578，2014年。
Courtesy CMB Carvalho and JR Lupski, and with the permission of Elsevier.承蒙CMB Carvalho与JR Lupski惠允，并获Elsevier出版社许可。
34 PHENOCOPIES
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Origins and Consequences of Chromosome Pathology 67 cortical asymmetries in the brain (Lin et al. 2015).染色体病理学的起源与后果 67 大脑皮质不对称性（Lin等，2015）。
The severe language disorder in one of the polysomic states, 49,XXXXY, may be due at least in part to poor development of the white matter tract from the language area (Broca’s area) of the frontal cortex to the premotor cortex (Dhakar et al. 2016).多体综合征（49,XXXXY）中出现的严重语言障碍，至少部分归因于从额叶皮质语言区（布罗卡区）到前运动皮质的白质束发育不良（Dhakar等，2016）。
Monosomy X, in contrast, has a high in utero lethality, although the small fraction surviving to term as females with Turner syndrome show, in contrast, a remarkably mild phenotype.相比之下，X单体在子宫内致死率很高，但少数存活至足月并表现为特纳综合征的女性，其表型却异常温和。
PHENOCOPIES Similar phenotypes may flow from different genotypes.表型模拟 相似的表型可能源于不同的基因型。
Syndromes resembling Silver-Russell syndrome, Prader-Willi syndrome, and Angelman syndrome, but due to other chromosomal imbalances, are described, and some examples are noted in Chapter 14 and Chapter 15. “Pseudotrisomy 13” might more usefully be known as holoprosencephaly and polydactyly syndrome (Bous et al. 2012).类似Silver-Russell综合征、Prader-Willi综合征和Angelman综合征但由其他染色体失衡引起的综合征已有描述，部分实例见第14章和第15章。“假性13三体”或许更应称为全前脑畸形并多指（趾）综合征（Bous等，2012）。
The expression “DiGeorge syndrome” refers to an ensemble of signs that characterize the 22q11 deletion.“DiGeorge综合征”一词指代一组表征22q11缺失的体征。
Somewhat similar clinical pictures can be seen in deletions of 10p13 and of 4q34.2.10p13缺失和4q34.2缺失可见部分相似的临床表现。
THE MOSAIC STATE Whether constitutional mosaicism matters depends upon which tissue, and how much of that tissue, is abnormal.嵌合状态 体质性嵌合是否重要，取决于异常涉及何种组织及其异常比例。
If a majority of the soma is chromosomally abnormal, then naturally the phenotype is likely to be abnormal.若体细胞大部分染色体异常，则表型自然可能异常。
If only a tiny fraction of some tissue were involved, in which the aneuploidy would have essentially no effect—if, for example, some of the bony tissue of the distal phalanx of the left little toe were trisomic 21, and the rest of the person 46,N—it would never be known.若仅涉及某组织极小部分，且非整倍体基本无影响——例如，左小趾远节指骨部分骨组织为21三体，而其余细胞为46,N——则此情况永不可知。
Indeed, as mentioned above, possibly everyone has mosaicism, essentially harmlessly, in certain tissues or organs.实际上，如上所述，可能每个人在某些组织或器官中都存在基本无害的嵌合体。
More to the point, a very minor degree of mosaicism could yet convey pathogenicity if a crucial tissue carried the imbalance.更关键的是，若关键组织携带失衡，极低程度的嵌合仍可能具有致病性。
An abnormal chromosome confined to tissues of, say, a localized area or cell type in one part of the brain, could theoretically cause neurological dysfunction (Rohrback et al. 2018; Graham et al. 2024).28 Mosaicism for a chromosome abnormality is detectable, using a sophisticated molecular approach, in normal adults, and a quarter of those analyzed in one study carried a “clonally-expanded mosaic chromosome alteration (mCA)” in at least one tissue (Gao et al. 2023).局限于大脑某局部区域或特定细胞类型的异常染色体，理论上可导致神经功能障碍（Rohrback等，2018；Graham等，2024）。28 通过精密分子方法，可在正常成人中检测到染色体异常的嵌合体；一项研究中分析的四分之一受试者至少在一个组织中携带“克隆扩增的嵌合染色体改变（mCA）”（Gao等，2023）。
The older the person, the more such mCAs.年龄越大，此类mCA越多。
These mCAs may have been expansions from a constitutional origin, or—more likely—may have arisen in post-natal life.这些mCA可能源于体质性扩增，或更可能发生于出生后。
The particular relevance of this state may be to do with cancer.此状态的特殊相关性可能与癌症有关。
Abnormality involving a gonad or part of a gonad (gonadal mosaicism) could lead to a child being conceived with that aneuploidy, as discussed above.涉及性腺或部分性腺的异常（性腺嵌合）可能导致子代受孕时携带该非整倍体，如前所述。
Mosaicism confined to extraembryonic tissue may be without phenotypic effect, although it can certainly 28 Mosaic aneuploidy of the brain arising in prenatal or post-natal life may be a basis of neurological disease, having somewhat of a parallel with the evolution of some cancers (Rosenkrantz and Carbone 2017); but here we are considering constitutional mosaicism generated in early embryonic life and established ab initio over the period of intrauterine brain development. 68 BASIC CONCEPTS cause anxiety if it produces an abnormal test result at prenatal diagnosis: This is confined placental mosaicism (CPM).局限于胚外组织的嵌合体可能无表型效应，但若在产前诊断中产生异常检测结果，则必然引起焦虑：即局限性胎盘嵌合体（CPM）。
CPM may exist unbeknownst in pregnancies producing normal infants, as Lestou et al. (2000) showed in a study of 100 placentas, with five revealing CPM for trisomies 2, 4, 12, 13, and 18.CPM可能存在于正常婴儿妊娠中而不为人知，如Lestou等（2000）对100个胎盘的研究所示，其中5个胎盘显示2、4、12、13和18三体的CPM。
Mosaicism may frequently be observed at the IVF laboratory at blastocyst biopsy: a state of affairs that becomes very relevant in preimplantation genetic testing (Chapter 23).在IVF实验室的囊胚活检中，嵌合体现象可能经常被观察到：这种情况在植入前遗传学检测中变得非常重要（第23章）。
Mosaicism for a Full Aneuploidy As a general principle, an individual with an aneuploid line in only some tissues is likely to have a less severe but qualitatively similar phenotype to someone with the non-mosaic aneuploidy.嵌合体全非整倍体
The ascertainment of these individuals is biased: those with a more obvious phenotypic defect are, naturally, more likely to be detected.这些个体的确定存在偏差：那些表型缺陷更明显的人，自然更容易被发现。
Mosaic Down syndrome—47,+21/46,N—can be less obvious than standard trisomy 21, and with a lesser compromise of intellectual function (Papavassiliou et al. 2015).嵌合型唐氏综合征——47,+21/46,N——可能不如标准21三体综合征明显，且智力功能受损程度较轻（Papavassiliou等，2015）。
The existence of 46,N cells in some of the brain tissue presumably has a moderating effect.某些脑组织中存在46,N细胞，推测具有调节作用。
Some aneuploidies can only, or almost only, exist in the mosaic state, the non-mosaic form being lethal in utero.某些非整倍体只能或几乎只能以嵌合状态存在，非嵌合形式在子宫内是致死的。
Examples of this are mosaic trisomies 8, 9, and 16.例如嵌合体三体8、9和16。
If the distribution of the aneuploid cell line is asymmetric, body shape may be asymmetric, generally with the hypoplasia present in regions of aneuploidy.如果非整倍体细胞系的分布不对称，体型可能也会不对称，通常非整倍体区域会出现发育不全。
De Ravel et al. (2001) described hemifacial microsomia (one side of the face being underdeveloped) and other body asymmetry in two children with autosomal mosaicism, one for trisomy 9, and the other trisomy 22.De Ravel等人（2001）描述了半侧颜面短小（面部一侧发育不良）及其他身体不对称现象，见于两名常染色体嵌合体儿童，其中一名为9号三体，另一名为22号三体。
The child with 47,XY,+22/46,XY had 9/10 cells + 22 on skin fibroblasts from the arm on the right (underdeveloped) side, compared with 5/11 on the left arm (the child’s blood karyotype was 46,XY).该患儿携带47,XY,+22/46,XY核型，其右侧（发育不全）手臂皮肤成纤维细胞中9/10的细胞存在+22，而左臂为5/11（患儿血液核型为46,XY）。
Molecular analysis supported there having been a post-zygotic anaphase lag that had produced the 46,XY line from an initially 47,XY,+22 conception.分子分析支持存在合子后后期延迟，该延迟从最初的47,XY,+22受精卵产生了46,XY细胞系。
Niessen et al. (2005) studied in some detail a girl with three shades of skin pigmentation—hypopigmented, normally pigmented, and hyperpigmented (“cutis tricolor”)—following the lines of Blaschko (see next section).Niessen等人（2005）详细研究了一名沿Blaschko线（见下一节）出现三种肤色色素沉着——色素减退、正常色素沉着和色素沉着过度（“三色皮肤”）——的女孩。
She karyotyped 45,X on blood, and 47,XX,+7 on skin biopsied from the darker skin.她血液的核型为45,X，而从较深色皮肤活检的皮肤核型为47,XX,+7。
A surprising case is that of Greally et al. (1996): a child with mosaic trisomy 16, a cardiac malformation, and otherwise (barring a unilateral simian crease) not dysmorphic, and her neurodevelopmental progress was quite normal.一个令人惊讶的案例是Greally等人（1996年）报告的：一名患有嵌合型16三体、心脏畸形，且除单侧猿线外无其他畸形的儿童，其神经发育进展相当正常。
One might suppose (but could not prove) that the trisomic cell line was confined in distribution and excluded the brain.可以推测（但无法证实）三体细胞系的分布局限于脑部之外。
Mosaicism excluding the bone marrow will give a normal blood karyotype, while mosaicism confined to marrow would be seen on routine peripheral blood analysis but not on other samplings; mosaic trisomy 8 may provide examples in both directions.骨髓嵌合体（不包括骨髓）将显示正常血染色体核型，而局限于骨髓的嵌合体可在常规外周血分析中观察到，但在其他样本中则不会；嵌合型8三体可能提供双向例证。
Examples of presumed very low-level trisomy mosaicism have come to light through prenatal diagnosis, such as trisomy 13 mosaicism in an apparently normal child with one cell out of 400 on cord blood (Delatycki et al. 1998; Figure 22–6).通过产前诊断发现了一些推测为极低水平三体嵌合体的案例，例如一名外表正常的新生儿脐带血中400个细胞里有一个细胞为13三体嵌合体（Delatycki等，1998；图22–6）。
In sex chromosome mosaicism, fertility can exist when otherwise infertility is the rule—for example, in “formes frustes” of Turner syndrome with 45,X/46,XX and of Klinefelter syndrome with 47,XXY/46,XY.在性染色体嵌合体中，当其他情况通常导致不育时，生育能力仍可能存在——例如，在45,X/46,XX的特纳综合征“顿挫型”和47,XXY/46,XY的克氏综合征中。
35 PHENOCOPIES
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Origins and Consequences of Chromosome Pathology 69 Mosaicism for a Structural Rearrangement Mosaicism for a classical structural rearrangement—a translocation, an inversion, a deletion, or a duplication—is rarely recognized.染色体病理学的起源与后果 69 结构重排的嵌合体 经典结构重排——易位、倒位、缺失或重复——的嵌合体很少被识别。
Kovaleva and Cotter (2016) reviewed 104 cases from the literature, either balanced or unbalanced.Kovaleva和Cotter（2016）回顾了文献中的104例病例，包括平衡型和非平衡型。
In the experience of one Australian laboratory, two cases of unbalanced translocation mosaicism were seen among 75,000 karyotypes from 1989 to 2013.根据一家澳大利亚实验室的经验，在1989年至2013年的75,000份核型中，发现了两例非平衡易位嵌合体。
One was a normal woman presenting with recurrent miscarriage, with 46,XX,der(6)t(6;8)(q27;q22.1)/46,XX; and the other was a globally delayed infant with 46,XY,der(22),t(14;22)(q32.1;q13.3)/46,XY (Dalzell et al. 2013).一例是表现为反复流产的正常女性，核型为46,XX,der(6)t(6;8)(q27;q22.1)/46,XX；另一例是全面发育迟缓的婴儿，核型为46,XY,der(22),t(14;22)(q32.1;q13.3)/46,XY（Dalzell等，2013）。
Molecular karyotyping increased the yield: in Francis et al. (2023), mosaic deletions and duplications were detected in 0.7% of clinical samples.分子核型分析提高了检出率：在Francis等人（2023）的研究中，临床样本中嵌合缺失和重复的检出率为0.7%。
With an unbalanced karyotype, the broad (indeed, obvious) rule applies, that the mosaic form is likely to be less severe than the non-mosaic form.对于非平衡核型，一个广泛适用（且显而易见）的规律是，嵌合形式可能比非嵌合形式症状更轻。
Pigmentary skin anomaly is a notable and clinically useful phenotypic trait that can characterize this type of unbalanced mosaicism, the important categories being hypomelanosis of Ito (Figure 3–22), linear and whorled nevoid hypermelanosis, and “phylloid” (leaf-like) pigmentary disturbance (Vreeburg and van Steensel 2012).色素性皮肤异常是一种显著且具有临床实用价值的表型特征，可用于表征这类非平衡嵌合体，主要类型包括伊藤色素减退症（图3–22）、线状和旋涡状痣样色素沉着过度，以及“叶状”色素紊乱（Vreeburg和van Steensel，2012）。
Figure 3–22.图3–22。
Hypomelanosis of Ito in a child with mosaicism 46,XX,dup(3)(q26.3qter)/ 46,XX. 70 BASIC CONCEPTS The distribution of the abnormal cells in hypomelanosis of Ito, and thus of dyspigmentation, follows the lines of Blaschko, and Magenis et al. (1999) use the expression “Blaschkolinear malformation complex.” Asymmetry is a further clinical pointer (Woods et al. 1994).一例嵌合体46,XX,dup(3)(q26.3qter)/46,XX儿童的伊藤色素减退症。 70 基本概念 伊藤色素减退症中异常细胞（以及由此产生的色素异常）的分布遵循Blaschko线，Magenis等人（1999）使用了“Blaschko线畸形复合体”这一表述。不对称性是另一个临床指征（Woods等，1994）。
An interesting category of mosaicism for a structural rearrangement is that in which two lines of opposite imbalance coexist, with or without a normal cell line as well.结构重排嵌合体中一个有趣的类别是两种相反不平衡的细胞系共存，可能伴有或不伴有正常细胞系。
Here, the error must have happened at a very early stage, and quite possibly, in those cases lacking a normal cell line, at the very first mitosis of the zygote.在这种情况下，错误必定发生在极早期阶段，并且很可能，在那些缺乏正常细胞系的病例中，错误发生在受精卵的第一次有丝分裂。
Such a case is described in Morales et al. (2007a), who analyzed a boy with the karyotype at birth of 46,XY,del(7q)/46,XY,dup(7q), although by age 12–14 months, the deletion cell line had disappeared, at least from blood and exfoliated urinary epithelial cells.Morales等人（2007a）描述了这样一个病例，他们分析了一名出生时核型为46,XY,del(7q)/46,XY,dup(7q)的男孩，尽管到12–14个月大时，缺失细胞系已消失，至少在血液和脱落尿路上皮细胞中如此。
Presumably, the karyotype at conception was 46,XY, but then the two chromosome 7 homologs underwent an unequal exchange of q21.1q31.3 material, generating, in the two daughter cells from the first mitosis, the deletion and duplication lineages.推测受孕时的核型为46,XY，但随后两条7号染色体同源物发生了q21.1q31.3区域的不等交换，在第一次有丝分裂的两个子细胞中产生了缺失和重复细胞系。
If, for example, the error had occurred one division later, at one of the two second mitotic divisions, a normal cell line might have been retained and have contributed to the inner cell mass.例如，如果错误发生在稍晚一次分裂，即第二次有丝分裂的其中一个细胞中，则可能保留一个正常细胞系，并参与内细胞团的形成。
Tissue Sampling in the Detection of Mosaicism Clearly, detecting—or failing to detect—a mosaic state will depend upon which tissue is studied and how many cells are counted/analyzed.检测嵌合体时的组织取样 显然，检测到或未能检测到嵌合状态取决于所研究的组织以及计数/分析的细胞数量。
Blood, buccal cells, amniocytes, chorionic villi, trophectoderm, skin fibroblasts, and urinary sediment cells have been the usually tested tissues.血液、颊黏膜细胞、羊水细胞、绒毛膜绒毛、滋养外胚层、皮肤成纤维细胞和尿沉渣细胞是通常检测的组织。
A normal blood result in a child with an indicative phenotype, or following an abnormal prenatal test, might then warrant testing other tissues.如果儿童具有提示性表型，或产前检测异常后血液结果正常，则可能需要检测其他组织。
Blood is a specialized tissue, and an abnormal cell line, otherwise widespread through the soma, can potentially be excluded from blood marrow following untold numbers of mitoses and if normal cells exert a superior survivability.血液是一种特化组织，异常细胞系即使广泛分布于体细胞中，也可能在无数次有丝分裂后，且正常细胞具有更强生存能力的情况下，被排除出骨髓。
Presumably this was the case, for example, in the child described in De Ravel et al. 2001 above, in whom skin fibroblasts, but not blood, retained the aneuploidy.例如，上述De Ravel等人（2001）描述的儿童很可能就是这种情况，其皮肤成纤维细胞保留了非整倍体，而血液则没有。
Skin fibroblast analysis has been a mainstay of mosaicism detection since the earliest days of cytogenetics (and actually predated the use of blood).自细胞遗传学早期以来，皮肤成纤维细胞分析一直是检测嵌合体的主要方法（实际上早于血液的使用）。
Another tissue of historic provenance is the buccal mucosa, the inner lining of the cheek obtained from a “cheek swab,” and this was the basis of a simple analysis of X chromosome aneuploidy via the demonstration of a compacted inactivated X (the Barr body)—a methodology little used these days.另一类具有历史渊源的组织是颊黏膜，即通过“口腔拭子”获取的颊内侧内衬组织，它曾是通过展示浓缩失活的X染色体（巴氏小体）来简单分析X染色体非整倍性的基础——这种方法如今已很少使用。
But this tissue has come to the forefront in the current century with the development of technologies to extract DNA from buccal mucosal cells that are contained in saliva, the “spit sample.” The buccal mucosal cells present in a saliva sample are representative of ectodermal tissue: the tissue from which, among others, the nervous system derives.但进入本世纪后，随着从唾液（即“唾液样本”）中所含颊黏膜细胞中提取DNA技术的发展，这类组织已跃居前沿。唾液样本中的颊黏膜细胞代表外胚层组织：神经系统等正是源自这类组织。
There is an obvious practical attraction in the ability to avoid even the (for most people) minor pain of a venipuncture, especially with children; no more is involved than simply spitting into a tube.能够避免（对大多数人而言）静脉穿刺带来的轻微疼痛，尤其对儿童而言，具有明显的实际吸引力；所需做的只是向试管中吐口水而已。
The DNA can then be subjected to a methodology such as single nucleotide polymorphism (SNP) chromosome microarray (CMA).随后可对DNA采用单核苷酸多态性染色体微阵列等方法进行分析。
The suitability of this approach was demonstrated in a landmark study in Francis et al. (2023), who compared the diagnostic utility of saliva-based against blood-based这种方法适用性在Francis等人（2023年）的一项里程碑式研究中得到证实，他们比较了基于唾液与基于血液的诊断效用。
36 PHENOCOPIES
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Origins and Consequences of Chromosome Pathology 71 CMA.染色体病理学的起源与后果 71 染色体微阵列分析。
In the analysis of 370 patients in a pediatric setting, including 224 presenting with syndromic or non-syndromic intellectual disability, in whom both types of testing were applied, the saliva-based test picked up 20 cases of mosaicism, a CNV or a trisomy, which were missed on the blood sampling.在对儿科环境中370名患者（包括224名表现为综合征性或非综合征性智力障碍的患者）的分析中，两种检测方法均被采用，基于唾液的检测发现了20例嵌合体、拷贝数变异或三体性病例，而这些病例在血液采样中被遗漏。
Notably, these mosaic cases were confined to the group of patients presenting with a syndromic intellectual disability. (For non-mosaic results, the blood and saliva samples were completely concordant.) These observations lead to the conclusion that saliva-based chromosome analysis should be a first-tier test, at least in the case of syndromic intellectual disability: that is to say, intellectual disability in the context of such other observations as organ malformation, facial and other dysmorphism, or growth disturbance.值得注意的是，这些嵌合体病例仅限于表现为综合征性智力障碍的患者群体。（对于非嵌合体结果，血液和唾液样本完全一致。）这些观察结果得出结论：基于唾液的染色体分析应作为一线检测手段，至少在综合征性智力障碍病例中如此——也就是说，智力障碍伴随其他观察结果如器官畸形、面部及其他形态异常或生长障碍的情况。
Gonadal (and Somatic-Gonadal) Mosaicism Gonadal mosaicism is suspected upon the observation of a chromosomally normal couple (at least on blood testing) having had two or more children with the same abnormal karyotype.性腺（及体细胞-性腺）嵌合体 当观察到染色体正常的夫妇（至少血液检测正常）生育了两个或更多具有相同异常核型的孩子时，可怀疑存在性腺嵌合体。
Molecular analysis can allow an inference of who is the carrier parent, such as Tosca et al. (2010) show in the family study of two children with a dup(4)(q22.2q32.3), in which the microsatellite pattern indicated a maternal origin.分子分析可推断谁是携带者父母，如Tosca等人（2010年）在对两名携带dup(4)(q22.2q32.3)的孩子的家庭研究中所示，其中微卫星模式表明母源起源。
In Kuroda et al. (2014), even though chromosome studies on the mother were normal, a maternal origin could be assumed in two siblings with Angelman syndrome due to a chromosome 15 inversion, which had deleted (among other genes) the UBE3A gene (Chapter 19).在Kuroda等人（2014年）的研究中，尽管母亲的染色体研究正常，但两名患有Angelman综合征的兄弟姐妹可假定为母源起源，原因是15号染色体倒位导致（除其他基因外）UBE3A基因缺失（第19章）。
Direct proof is provided by analysis of gametes.直接证据来自配子分析。
For example, in a case that had come to notice through an IVF clinic, Somprasit et al. (2004) report a couple having had a 21q duplication in two embryos subjected to PGT, and then showed the same duplication in 6.6% of 1,002 of the father’s sperm.例如，在一个通过试管婴儿诊所引起注意的案例中，Somprasit等人（2004年）报告一对夫妇在两名接受胚胎植入前遗传学检测的胚胎中出现了21q重复，随后在父亲1002个精子中的6.6%中发现了相同的重复。
The abnormality was not present in his blood.该异常未出现在他的血液中。
Similarly, Alkaya et al. (2020) describe a father of three children with cri du chat syndrome (Chapter 14) due to an unbalanced translocation t(5;19)(p13.3;q13.4); the translocation was present in his sperm, but in neither blood nor skin biopsy.类似地，Alkaya等人（2020年）描述了一名父亲，其三个孩子因不平衡易位t(5;19)(p13.3;q13.4)而患有猫叫综合征（第14章）；该易位存在于他的精子中，但血液和皮肤活检中均未发现。
Somatic-gonadal mosaicism can be inferred on the observation of one parent of an aneuploid child carrying, in mosaic state, the same aneuploidy.体细胞-性腺嵌合体可根据观察到非整倍体孩子的一名父母以嵌合状态携带相同非整倍体而推断。
Sachs et al. (1990) studied a mother who had had one Down syndrome child and three other trisomic 21 pregnancies, and her blood karyotype was 47,+21[3%]/46,N[97%].Sachs等人（1990年）研究了一名母亲，她曾生育一个唐氏综合征孩子并有其他三次21三体妊娠，其血液核型为47,+21[3%]/46,N[97%]。
Ovarian biopsies showed almost half the cells in each ovary to be 47,XX,+21.卵巢活检显示每个卵巢中近一半细胞为47,XX,+21。
We have seen a similar case, a woman who presented having had two trisomic 21 pregnancies.我们曾见过一个类似病例，一位女性曾两次怀有21三体妊娠。
On blood with a 60-cell count, she and her partner were non-mosaic 46,N.在60个细胞计数的血液检测中，她及其伴侣均为非嵌合体46,N。
She recounted a story that her own mother had had an amniocentesis when pregnant with her, which had shown a single + 21 cell.她讲述了一个故事：她的母亲在怀她时曾做过羊膜穿刺，结果显示有一个+21细胞。
Given this information, “spit sample” microarray was done, and she proved to have ~5% of cells trisomic, inferentially revealing her state of somatic-gonadal mosaicism.根据这一信息，进行了“唾液样本”微阵列分析，结果证明她约有5%的细胞为三体，推断揭示了她处于体细胞-性腺嵌合状态。
Figure 3–23 shows an example of somatic-gonadal mosaicism for a structural rearrangement, del(1).图3-23展示了一个结构重排del(1)的体细胞-性腺嵌合示例。
The index case was identified with a small intrachromosomal del(1) at routine prenatal diagnosis.先证者在常规产前诊断中被发现存在一个小型染色体内del(1)。
The father was mosaic for this deletion in 20% of lymphocytes.父亲在20%的淋巴细胞中嵌合了该缺失。
Of his two other children, one had normal chromosomes, and the other had the same deletion.他的另外两个孩子中，一个染色体正常，另一个有相同的缺失。
The father is phenotypically normal, and the older child with the deletion has an IQ in the low normal range.父亲表型正常，而带有缺失的年长孩子智商处于正常低值范围。
A similar circumstance is recorded in Fan et al. (2001): A university-educated man working as a financial planner, having the blood karyotype 46,XY,dup(8)(p21.3p23.1)[6]‌/46,XY[24], fathered two daughters 72 BASIC CONCEPTS with 46,XX,dup(8)(p21.3p23.1).类似情况记录于Fan等人（2001年）的研究中：一位受过大学教育、担任财务规划师的男性，血液核型为46,XY,dup(8)(p21.3p23.1)[6]‌/46,XY[24]，生育了两个女儿 72 基本概念 她们核型为46,XX,dup(8)(p21.3p23.1)。
These girls had poor language development, clumsy motor abilities, and minor facial dysmorphism.这些女孩语言发育不良、运动能力笨拙，并有轻微面部畸形。
Pitt-Hopkins syndrome (Chapter 14) is due to an 18q microdeletion, and normal parents are on record as having him- or herself a low-level mosaicism demonstrable on blood (Figure 14–73) (Doudney et al. 2013; Kousoulidou et al. 2013) or on blood, urinary, and salivary (but not hair) cells (Steinbusch et al. 2013).Pitt-Hopkins综合征（第14章）由18q微缺失引起，正常父母有记录显示其自身在血液中（图14-73）（Doudney等人2013年；Kousoulidou等人2013年）或在血液、尿液和唾液（但非毛发）细胞中（Steinbusch等人2013年）存在低水平嵌合。
Mosaicism at Prenatal Diagnosis About 1%–2% of placentas can have a different chromosomal constitution from that of the embryo, with usually the embryo being normal and the placenta trisomic.产前诊断中的嵌合现象 约1%–2%的胎盘可能具有与胚胎不同的染色体组成，通常胚胎正常而胎盘为三体。
This is “confined placental mosaicism.” Thus, in 1%–2% of chorionic villus sampling (which can be considered a placental biopsy) or in noninvasive prenatal testing (which can be considered, in a sense, as a “wet” chorionic villus sampling), there will be a potentially misleading result.这被称为“限制性胎盘嵌合”。因此，在1%–2%的绒毛膜绒毛取样（可视为胎盘活检）或无创产前检测（某种意义上可视为“湿性”绒毛膜绒毛取样）中，可能会出现潜在误导性结果。
Fortunately, these uncommon instances can, as a rule, be recognized as such, although often not without causing some anxiety at the time.幸运的是，这些不常见的情况通常可以被识别出来，尽管往往会在当时引起一些焦虑。
In a few confined placental aneuploidies, the function of the placenta may be compromised, and fetal well-being may be affected.在少数限制性胎盘非整倍体中，胎盘功能可能受损，胎儿健康可能受到影响。
Infrequently, true mosaicism is recognized at amniocentesis.在羊膜穿刺中，偶尔会识别出真正的嵌合体。
Occasional cells with a chromosomal abnormality, if they are solitary or involving a single clone, are generally regarded as having arisen in vitro (“artifactual mosaicism”).如果出现染色体异常的零星细胞，且为孤立或单一克隆，通常被认为是在体外产生的（“人工嵌合”）。
At least most of the time, Figure 3–23.至少大多数情况下，图3-23。
Somatic-Gonadal Mosaicism.体细胞-性腺嵌合。
A family exemplifying somatic-gonadal mosaicism. (a) Pedigree.一个体现体细胞-性腺嵌合体的家庭。(a) 家系图。
The father had the mosaic karyotype 46,XY,del(1)(q25q31.2)[16]/46,XY[4]‌ on lymphocyte study.父亲在淋巴细胞研究中发现嵌合核型46,XY,del(1)(q25q31.2)[16]/46,XY[4]。
Two children have the del(1)(q25q31.2) in nonmosaic state.两个孩子以非嵌合状态携带del(1)(q25q31.2)。
The family was ascertained following routine prenatal diagnosis.该家庭是在常规产前诊断后发现的。
The older sibling’s development was judged, at age 5 years, to be in the low average range; height, weight, and head circumference were in the range 20–25th centiles.年长同胞在5岁时发育评估为低平均范围；身高、体重和头围位于20-25百分位。
The father worked as an electrician. (b) Partial karyotype showing the father’s two cell lines: two normal no. 1 chromosomes, and one normal and one deleted chromosome 1.父亲是一名电工。(b) 部分核型显示父亲的两个细胞系：两条正常的1号染色体，以及一条正常和一条缺失的1号染色体。
The segment 1q25q31.2 is shown cross-hatched. (Courtesy G Dawson.)1q25q31.2片段以交叉阴影线标示。(承蒙G Dawson提供。)
37 FUNCTIONAL IMBALANCE
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Origins and Consequences of Chromosome Pathology 73 this is probably the correct interpretation (but see the case in Somatic-gonadal mosaicism above).染色体病理的起源与后果 73 这可能是正确的解释（但见上文体细胞-性腺嵌合体中的病例）。
We consider mosaicism at prenatal diagnosis in detail in Chapter 22.我们在第22章详细讨论产前诊断中的嵌合体。
FUNCTIONAL IMBALANCE The idea that abnormality could be due to unequal parental contributions of an overall correct amount of chromosome material seemed most remarkable in 1980 when Engel first made the suggestion and coined the expression “uniparental disomy.” It came to be accepted fact.功能失衡 认为异常可能源于父母对总量正确的染色体物质贡献不均的想法，在1980年恩格尔首次提出并创造“单亲二体”一词时显得极为引人注目。它后来成为公认的事实。
The two disorders that, par excellence, exemplify the concept of qualitative imbalance are Prader-Willi syndrome (PWS) and Angelman syndrome (AS).最能体现定性失衡概念的两个疾病是普拉德-威利综合征和安吉尔曼综合征。
The concept of genomic imprinting, discussed above, is central to an understanding of the etiology.上文讨论的基因组印记概念是理解病因的核心。
Each syndrome is due to the non-expression of different (but neighboring) segments within the proximal long arm of chromosome 15.每种综合征均由15号染色体近端长臂内不同（但相邻）片段的不表达引起。
A “PWS critical region” is normally expressed from only one chromosome, in this case the paternally originating chromosome.“PWS关键区域”通常仅由一条染色体表达，在此情况下为父源染色体。
The maternal-originating region is normally inactive, and alleles in this region are not transcribed.母源区域通常处于失活状态，该区域的等位基因不会被转录。
Thus, there is a “functional monoallelism.” If the paternal PWS region is absent, the maternal one cannot “fill the gap,” and the consequential functional nullisomy is the root cause of PWS.因此存在“功能性单等位基因表达”。如果父源PWS区域缺失，母源区域无法“填补空缺”，由此导致的功能性零染色体是PWS的根本原因。
An “AS critical region” exists, lying just a little distal from the PW region.存在一个“AS关键区域”，位于PW区域稍远端。
Likewise, it needs only monoallelic expression for normal phenotypic function.同样，正常表型功能仅需单等位基因表达。
In this case, it is the maternal region that is active, and the paternal region, having been imprinted, is inactive.在这种情况下，母源区域处于活跃状态，而父源区域因印记作用而失活。
If the maternal region is absent there can be no genetic activity, and this causes the AS phenotype.如果母源区域缺失，则无法产生遗传活性，从而导致AS表型。
Absence of the paternal PWS region or maternal AS region can flow from two major mechanisms.父源PWS区域或母源AS区域的缺失可能源于两种主要机制。
First, in UPD, the chromosome 15 from one parent is lacking, and the “correcting” presence of two copies from the other parent cannot restore a proper balance.首先，在UPD中，来自一方亲本的15号染色体缺失，而另一方亲本的两条染色体“代偿性”存在无法恢复适当平衡。
This can be heterodisomy (the two homologs being different) or isodisomy (they are identical).这可能是异源二体（两条同源染色体不同）或同源二体（两条同源染色体相同）。
Second, there can be a deletion within proximal 15q that removes a segment of chromatin containing the PWS and AS regions.其次，15q近端区域可能发生缺失，移除包含PWS和AS区域的染色质片段。
These issues are dealt with in some detail in Chapter 19.这些问题将在第19章详细讨论。
Uniparental disomy for the entire chromosome set—“uniparental diploidy”—has a devastating effect on development.整条染色体的单亲二体——“单亲二倍体”——对发育具有毁灭性影响。
If a conceptus has lost its maternal complement, and the paternal complement is doubled, embryonic development arrests, leaving only grossly abnormal chorionic villi comprising the pregnancy.如果胚胎失去母源染色体组而父源染色体组加倍，胚胎发育停滞，仅留下严重异常的绒毛膜绒毛构成妊娠物。
This is a hydatidiform mole (Chapter 20).这就是葡萄胎（第20章）。
If a 46,XX ovum at meiosis I attempts a parthenogenetic development, a grossly disorganized mass of embryonic tissue results: an ovarian teratoma.如果46,XX卵母细胞在减数第一次分裂时尝试孤雌发育，会产生高度紊乱的胚胎组织团块：卵巢畸胎瘤。
If a triple set of chromosomes (triploidy) is present at conception, there is either a diploid maternal set plus a haploid paternal set or vice versa.如果受孕时存在三组染色体（三倍体），则要么是二倍体母源组加单倍体父源组，反之亦然。
These different parental origins determine quite different but very abnormal fetal and placental phenotypes (Chapter 13).这些不同的亲本来源决定了截然不同但高度异常的胎儿和胎盘表型（第13章）。
As the imprinting story has evolved, it has emerged that most of the genome appears not to be subject to imprinting.29 For most chromosomes and with both homologs equally genetically active, regardless of the parent of origin, UPD will have no untoward effect.随着印记研究的深入，发现大部分基因组似乎不受印记影响。29 对于大多数染色体，无论亲本来源如何，两条同源染色体均具有同等遗传活性，UPD不会产生不良影响。
Only if the UPD-contributing parent should happen to be heterozygous for a recessive gene, and if this is the isodisomy category of UPD, will the child be affected, 29 Several small segments across the karyotype show an imprinting effect, but a clinical implication of this remains uncertain (Joshi et al. 2016; and see Figure 19–2).只有当提供UPD的亲本恰好是隐性基因杂合子，且属于同源二体类UPD时，子代才会患病。29 核型中若干小片段显示印记效应，但其临床意义仍不确定（Joshi等，2016；见图19-2）。
38 SPORADIC AND RECURRENT ABNORMALITIES
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74 BASIC CONCEPTS displaying the Mendelian condition concerned due to homozygosity (“isohomozygosity”) for that recessive gene.74 基本概念 显示因该隐性基因纯合（“等位纯合”）而表现出的孟德尔性状。
Rare instances of this scenario are known.这种情况的罕见实例是已知的。
Similar considerations may apply in the trisomies.类似的考虑可能也适用于三体综合征。
Naturally, one parent must have contributed more than one homolog.自然，一个亲本必须贡献了不止一个同源体。
Considering the example of Down syndrome, does the parent from whom the disomic gamete came contribute two different chromosome 21s?以唐氏综合征为例，产生二体配子的亲本是否贡献了两条不同的21号染色体？
In other words, does the child inherit a chromosome 21 from three of the grandparents—“heterotrisomy”?换句话说，这个孩子是否从三位祖父母那里各继承了一条21号染色体——“异源三体”？
Or does the parent contribute two identical (isodisomic) chromosome 21s?或者父母贡献了两条相同的（同源二体）21号染色体？
Whether phenotypic differences may flow from these different possibilities is quite uncertain, although Baptista et al. (2000) suggest that heterotrisomy 21 may, of itself, convey a greater risk for a specific heart malformation, ventricular septal defect, speculatively due to a damaging interaction of three subtly different protein products from a 21q “heart locus.” Segmental Uniparental Disomy A mitotic mechanism that can lead to functional imbalance, if the segments exchanged are in a region subject to imprinting, is somatic recombination.这些表型差异是否源于这些不同的可能性尚不确定，尽管Baptista等人（2000）提出，21号染色体异源三体本身可能增加特定心脏畸形（室间隔缺损）的风险，推测是由于来自21q“心脏位点”的三个细微不同的蛋白质产物产生了有害相互作用。
The first shown example of this causing a dysmorphic syndrome is the segmental paternal uniparental disomy for 11p that underlies some Beckwith-Wiedemann syndrome, 11p being a segment that is normally maternally imprinted.导致畸形综合征的第一个例子是11p的节段性父源单亲二倍体，这是某些贝克威斯-威德曼综合征的基础，而11p通常是一个母源印记的节段。
In the partial UPD(pat) cell line, this segment will now be expressing biallelically at distal 11p, instead of the normal monoallelic expression.在部分UPD(pat)细胞系中，该片段现在将在11p远端区域双等位表达，而非正常的单等位表达。
The asymmetry of body growth that may be observed in this syndrome reflects the body distribution of two cell lineages: the normal biparental disomic line, and the functionally imbalanced UPD(pat) line.在该综合征中可能观察到的身体生长不对称反映了两种细胞谱系在体内的分布：正常的双亲二体细胞系和功能失衡的父源单亲二倍体细胞系。
SPORADIC AND RECURRENT ABNORMALITIES Chromosomally normal parents can produce abnormal gametes by nondisjunction, rearrangement, or one of the other mutational mechanisms we have discussed above.散发性与复发性异常 染色体正常的父母可能通过不分离、重排或我们上文讨论的其他突变机制产生异常配子。
The combination of factors that causes these defects in an individual case is unknown.导致个体案例中出现这些缺陷的因素组合尚不明确。
No convincing case has ever been made for an important agency of diet, illness, chemical exposure, or “lifestyle factors” in maternal chromosome 21 meiotic nondisjunction (Chapter 26), nor is there much support from epidemiological studies (Chapter 13).在母体21号染色体减数分裂不分离（第26章）中，从未有令人信服的证据表明饮食、疾病、化学物质暴露或“生活方式因素”是重要原因，流行病学研究（第13章）也未能提供太多支持。
Noting the similarity of Down syndrome prevalence rates worldwide, Carothers et al. (1999) comment that “the totality of published data could well be consistent with no real variation at all, and [this] might explain why a search for environmental factors associated with Down syndrome has been so unproductive.” The maternal age effect is of course important, indeed central, and any search for causes of chromosomal aneuploidy must take this into account.注意到唐氏综合征在全球范围内的患病率相似，Carothers等人（1999）评论道：“已发表的全部数据很可能与不存在真正差异的情况一致，[这]或许可以解释为何寻找与唐氏综合征相关的环境因素一直如此徒劳无功。”母体年龄效应当然重要，甚至至关重要，任何对染色体非整倍体病因的探索都必须考虑到这一点。
A plausible view is that there is a natural degeneration of the oöcyte, as we discussed above, and with reference to Figure 3–13.一种合理的观点是，卵母细胞存在自然的退化过程，正如我们上文所讨论的，并参考图3-13所示。
Simply put, eggs get older, and they show their age.简单来说，鸡蛋会变老，并且会显露出老化的迹象。
Chromosomes are plastic, dynamic entities, and cell division is a complex mechanical process; and these qualities alone may suffice to endow the vulnerability that causes human aneuploidy and rearrangement.染色体是可塑的、动态的实体，细胞分裂是一个复杂的机械过程；仅这些特性就足以赋予导致人类非整倍体和重排的脆弱性。
Given the assumption that all persons with intact gametogenesis are capable of producing an abnormal gamete, one view is Origins and Consequences of Chromosome Pathology 75 that it may simply be so, that a certain background abnormality rate is intrinsic to the human species and at least in the majority of cases, it is a chance matter whether this or that couple will have the misfortune to conceive the abnormality which, inevitably, someone has to bear.假设所有具有完整配子发生能力的人都可能产生异常配子，一种观点认为 染色体病理学的起源与后果 75 即情况可能本就如此：一定背景下的异常率是人类物种固有的，至少在大多数情况下，某对夫妇是否会不幸怀上某种异常（而此种异常不可避免地必须由某人承受）纯属偶然。
Parental Predisposition to Nondisjunction or Deletion/Duplication?父母对不分离或缺失/重复的易感性？
An alternative view is that some 46,XX and 46,XY people are more prone than others to produce chromosomally unbalanced gametes.另一种观点认为，某些46,XX和46,XY个体比其他个体更容易产生染色体不平衡的配子。
An intrinsic fault, or at least a vulnerability, in the mechanism of chromosome distribution at cell division could be the basis of the rare examples of recurring defects.细胞分裂时染色体分布机制的内在缺陷，或至少是脆弱性，可能是罕见反复出现缺陷的基础。
The synaptonemal complex gene SYPC3, and the mismatch repair genes, with particular reference to MLH1 (otherwise familiar to the counselor in Lynch syndrome) and MLH3, and the related meiosis genes MSH4 and MSH5, would all be plausible candidates in which subtle variation might affect integrity (Singh et al. 2021).联合复合体基因SYPC3，以及错配修复基因（特别是咨询师在Lynch综合征中熟悉的MLH1）和MLH3，还有相关的减数分裂基因MSH4和MSH5，都可能是其中细微变异会影响完整性的合理候选基因（Singh等人，2021年）。
Given the complexity of the apparatus and process of meiotic cell division, it is logical that error-causing mutants in the controlling genes (whether or not this might include any of the aforementioned) would exist.鉴于减数分裂细胞分裂的装置和过程之复杂性，控制基因中（无论是否可能包括上述任何基因）存在导致错误的突变体是合乎逻辑的。
Whether there might be milder alleles at postulated cell-division or recombination loci, which could more widely be the cause of occasional nondisjunction or del/dup, remains a matter for speculation.在假定的细胞分裂或重组位点是否存在更温和的等位基因，从而可能更广泛地导致偶发的染色体不分离或缺失/重复，仍是一个推测性问题。
A genome-wide association study for genes associated with maternal nondisjunction of chromosome 21 identified some loci of interest, but none were conclusive (Chernus et al. 2019).一项关于与母亲21号染色体不分离相关基因的全基因组关联研究识别出了一些感兴趣的位点，但均未得出确凿结论（Chernus等人，2019年）。
Nevertheless, a geneticist could scarcely ignore that there might exist subtle genetic variation potentially setting the stage for chromosomal aberration.然而，遗传学家几乎无法忽视可能存在细微的遗传变异，从而为染色体畸变埋下伏笔。
A Note on the Diagrams.关于图表的说明
Following the progress of rearranged chromosomes during meiosis is not easy, so we have taken some liberties in simplifying the diagrams.在减数分裂过程中追踪重排染色体的进展并不容易，因此我们在简化图表时采取了一些灵活处理。
Most of these diagrams depict the synapsing chromosomes at meiosis with just one chromatid; of course, the chromosome has actually replicated at this point and exists as a double-chromatid entity (Figure 3–24).大多数这些图表描绘了减数分裂中仅含一条染色单体的联会染色体；当然，染色体在此阶段实际上已经复制，并以双染色单体的形式存在（图3–24）。
Figure 3–24.图3–24。
Chromosomes at synapsis exist as double-chromatid structures (e.g., the reciprocal translocation quadrivalent at right).联会时的染色体以双染色单体结构存在（例如右侧的相互易位四价体）。
But, for simplicity, we generally represent them with just the one chromatid (left).但为简便起见，我们通常仅用一条染色单体（左侧）来表示它们。

4 Chapter 4

39 DIFFERENT TYPES OF RISK FIGURE
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4 DERIVING AND USING A RISK FIGURE RISK IS A CENTRAL CONCEPT in genetic counseling.4 推导与使用风险数值 风险是遗传咨询中的核心概念。
By risk, we mean the probability that a particular event will happen.风险，我们指的是某一特定事件发生的概率。
Probability is conventionally measured with a number ranging from 0 to 1.概率通常用0到1之间的数字来衡量。
A probability (p) of zero means never, and a probability of 1 means always.概率（p）为0意味着从不发生，概率为1意味着总是发生。
For two or more mutually exclusive possible outcomes, the individual probabilities sum to 1.0 (or 100%).对于两个或多个互斥的可能结果，各个概率之和为1.0（或100%）。
Thus, someone who is a heterozygote for a particular chromosomal rearrangement might, in any given pregnancy, have a probability of 0.10 (10%) of having an abnormal child and a probability of 0.90 (90%) of having a normal child.因此，某个特定染色体重排的杂合子携带者，在任何一次妊娠中，生出异常孩子的概率为0.10（10%），生出正常孩子的概率为0.90（90%）。
We may speak in terms of risks of recurrence or of occurrence: the probability that an event will happen again, or that it will happen for the first time.我们可以用复发风险或发生风险来表述：即事件再次发生的概率，或首次发生的概率。
Risk can also be presented as odds: the ratio of two mutually exclusive probabilities.风险也可以表示为几率：两个互斥概率的比率。
The odds for the hypothetical heterozygote just mentioned would be 9:1 in favor of a normal child.前述假设的杂合子生出正常孩子的概率为9:1。
The word risk has two important meanings in the English language.风险这个词在英语中有两个重要的含义。
First, there is the scientific sense of probability that we already discussed.首先，有我们已经讨论过的概率的科学意义。
Second, as most people use the word, it conveys a sense of exposure to danger.其次，正如大多数人使用这个词时所理解的那样，它传达了一种暴露于危险之中的感觉。
Our hypothetical heterozygote runs the risk that an unfortunate outcome may occur (an abnormal child, or an abnormal result at prenatal diagnosis).我们假设的杂合子面临着不幸结果可能发生的风险（例如生出异常的孩子，或在产前诊断中出现异常结果）。
In the genetic counseling clinic, these meanings of risk coalesce in some ways, to which the counselor needs to be sensitive.1 We might instead use such everyday words as chance or likelihood, which have no negative connotation, to refer to the fortunate outcome of normality.在遗传咨询诊所中，这些风险的含义以某种方式汇聚在一起，咨询师需要对此保持敏感。我们或许可以用“机会”或“可能性”这类日常用语（它们没有负面含义）来指代正常的幸运结果。
The words fortunate and unfortunate are also chosen deliberately: The wanted or the unwanted event will occur entirely by chance, analogous to tossing a coin, throwing a dice, or being dealt a card.“幸运”与“不幸”这两个词也是经过刻意选择的：期望或不期望的事件将完全随机发生，类似于抛硬币、掷骰子或发牌。
DIFFERENT TYPES OF RISK FIGURE Geneticists arrive at risk figures in a number of ways (Clarke 2019), two of which, empiric and Mendelian, have particular application to cytogenetics. 1.不同类型的风险数据 遗传学家通过多种方式得出风险数据（Clarke 2019），其中经验风险和孟德尔风险两种方法在细胞遗传学中具有特殊应用。
Empiric risks.经验风险。
In the great majority of chromosomal situations, no clear theory exists from which a risk figure can be derived, and one must observe what has happened previously (as far as one can judge) in the same situation in other families and make an extrapolation to the family in question.在绝大多数染色体情况下，并不存在明确的理论可以据此推导出风险数值，而必须观察（尽己所能判断）其他家庭在相同情况下先前发生的情况，并将此推论应用于所讨论的家庭。
Empiric risks thus appeal to experience, and they only estimate the intrinsic, true probability.经验风险因此诉诸于经验，且它们仅估计内在的真实概率。
The data may be available in the literature record or in specific databases; or the counselor may need to derive a “private estimate” from an analysis of the client’s family.数据可能存在于文献记录或特定数据库中；或者咨询师可能需要通过分析客户的家庭情况得出一个“私人评估”。
The 1 There has been a move in the UK to replace the word risk with the word chance when used in the context of prenatal screening, prompted by opinions from some parents of children with Down syndrome.在英国，一些唐氏综合征患儿的家长提出意见后，产前筛查语境中已出现用“机会”一词替代“风险”的趋势。
Wald et al. (2022) disagree, even seeing Orwellian overtones, arguing that “risk” and “chance” are not perfect synonyms, and the subtle distinction in meaning is important in the public understanding of prenatal screening. 78 BASIC CONCEPTS risk estimate has a greater or lesser degree of precision depending on how much data has been accumulated upon which the estimate is based. 2.Wald等人（2022）对此持不同意见，甚至认为其中带有奥威尔式的意味，主张“风险”与“几率”并非完全同义词，其细微的语义差异对公众理解产前筛查至关重要。 78 基本概念 风险估计的精确度高低取决于该估计所依据的数据积累量。
Mendelian risks.孟德尔遗传风险。
If a clear model of inheritance is known, risk figures derived by reference to that theory may be used.如果已知明确的遗传模式，则可参照该理论推导出的风险数据进行使用。
In practice, only Mendel’s law of segregation is applied in this context.在实践中，孟德尔分离定律仅适用于此情境。
When a pair of homologous chromosomes segregates at meiosis, which chromosome enters the gamete that will produce the conceptus is typically a random matter.当一对同源染色体在减数分裂时分离，哪个染色体进入将产生胎儿的配子通常是随机的。
Each has an equal chance: a probability of 0.5.每个染色体有同等机会：概率为0.5。
Thus, a parent who carries a microdeletion 16p11.2 has a 50/50 likelihood to transmit this chromosome to a child, a 1:1 segregation.因此，携带16p11.2微缺失的父母有50%的概率将该染色体传给子女，即1:1分离。
This is assumed to be a true risk, not an estimate: It is 0.5 exactly.这被认为是真实风险，而非估计值：确切为0.5。
Consider, for example, the common situation of a young couple having had a child with Down syndrome.例如，考虑一对年轻夫妇生下一个唐氏综合征患儿的常见情况。
Nothing is known about nondisjunction that could provide a theoretical model on which to base a recurrence risk figure.目前尚无关于不分离现象的理论模型可用来推算复发风险值。
We therefore use empiric data—that is, information obtained from surveying large numbers of other such families.因此我们使用经验数据——即通过调查大量其他类似家庭获得的信息。
It may be observed, for example, that in these families about one pregnancy in 100, subsequent to the index case of Down syndrome, produced another child with Down syndrome.例如，可能观察到在这些家庭中，继首例唐氏综合征患儿之后，约每100次妊娠中有一次会再次生出唐氏综合征患儿。
Formally expressed, this is a segregation analysis.正式表达即为分离分析。
From this rate of 1/100 we can derive a risk figure of 1%, which we then have as the basis for advising patients. (Actually, it is not quite as straightforward as this in Down syndrome; see Chapter 13.) If a theoretical construct can be applied, this may allow a more precise calibration of the empiric figure.根据1/100的比率，我们可得出1%的风险值，并以此为基础为患者提供咨询。（实际上，唐氏综合征的情况并非如此简单；见第13章。）如果能够应用理论模型，则可能对经验数据进行更精确的校准。
The del 17q21.31 of Koolen-de Vries syndrome (Chapter 14), which has a population frequency of 1/16,000, offers an example.Koolen-de Vries综合征（第14章）的17q21.31缺失，其人群频率为1/16,000，提供了一个例子。
This particular deletion may have, as a necessary but not sufficient basis for its generation, a 17q inversion encompassing the length of the deleted segment (chr17:45.6-46.1 Mb).这种特定缺失的产生可能以包含缺失片段长度（chr17:45.6-46.1 Mb）的17q倒位为必要但非充分条件。
The risk is related to the inversion status of the parents, the dimorphism referred to as H1 (normal 17q21.31 sequence, N) and H2 (inverted 17q21.31 sequence, V).风险与父母的倒位状态相关，即二态性H1（正常17q21.31序列，N）和H2（倒位17q21.31序列，V）。
Koolen et al. (2012) apply some fundamental genetic concepts in order to tailor the risk figure according to the possible parental inversion genotypes, NN, NV, and VV, and thus the six possible mating combinations: NN × NN, NN × NV, NV × NV, NN × VV, NV × VV, and VV × VV.Koolen等人（2012）应用一些基本遗传学概念，根据父母可能的倒位基因型NN、NV和VV，以及由此产生的六种可能婚配组合：NN×NN、NN×NV、NV×NV、NN×VV、NV×VV和VV×VV，来定制风险值。
The adjusted risk figures of 0.03% (for VV × VV parents) and 0.008% (NN × NV parents), versus the population figure of 0.006%, barely dent the >99.9% chance of non-recurrence, but the principle behind the exercise is to be acknowledged.调整后的风险值0.03%（VV×VV父母）和0.008%（NN×NV父母），相对于人群风险值0.006%，几乎未改变>99.9%的不复发概率，但这一分析背后的原则值得认可。
A somewhat similar approach may apply to the inverted duplication of 8p (inv dup 8p), as discussed on Chapter 14.类似方法可能适用于8p倒位重复（inv dup 8p），如第14章所述。
An inversion polymorphism at chr8:7.6-12.3 Mb, which has a high (26%) frequency in the general population, predisposes to a misalignment during meiosis (Giglio et al. 2001).chr8:7.6-12.3 Mb处的倒位多态性在一般人群中频率较高（26%），易导致减数分裂时排列错位（Giglio等人，2001）。
Indeed, generation of the rearrangement may only be possible in the setting of this parental inversion.事实上，这种重排的产生可能仅在存在这种父母倒位的情况下才可能发生。
However, the absolute risk among this quarter of the (at least European) population must remain extremely low, given the rarity with which the inv dup 8p is seen, and the absence of any report of recurrence.然而，鉴于inv dup 8p极为罕见且无复发报告，在这四分之一（至少是欧洲）人群中，绝对风险必然极低。
The risk to the non-carrier may be a true 0.0%.对非携带者的风险可能确实是0.0%。
Likewise, for the circumstance of the parent heterozygous for a chromosomal rearrangement, the counselor can consult data that have been accumulated by workers in the field, foremost among whom, in respect of reciprocal translocations, are Stengel-Rutkowski et al. (1988), Cohen et al. (1992, 1994), and Midro et al. (2000).同样，对于染色体重排杂合子父母的情况，咨询师可以查阅该领域研究者积累的数据，其中关于相互易位的最重要研究者包括Stengel-Rutkowski等人（1988年）、Cohen等人（1992年、1994年）以及Midro等人（2000年）。
Since almost由于几乎
40 DIFFERENT TYPES OF RISK FIGURE
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Deriving and Using a Risk Figure 79 all reciprocal translocations are unique to one family, it is not necessarily simple to estimate a figure for a family with a “new” translocation, but an attempt can be made (see Chapter 5).推导和使用风险数值 79所有相互易位对每个家庭都是独特的，为一个有“新”易位的家庭估算数值并不一定简单，但可以尝试（见第5章）。
On the other hand, for the Robertsonian translocations, each type of which can generally be regarded as the same between families, extrapolation of risk figures from historical data to a current family is usually valid.另一方面，对于罗伯逊易位，每种类型通常可视为在不同家庭间相同，因此从历史数据向当前家庭外推风险数值通常是有效的。
Risk may apply more generally in the sense of a successful or unsuccessful outcome.风险可能更广义地适用于成功或失败的结果。
Consider the case of couples having had a previous aneuploid pregnancy and now seeking blastocyst testing to be sure of avoiding a recurrence: What are their odds of having a euploid blastocyst, suitable for transfer?考虑那些曾有过非整倍体妊娠、现在寻求囊胚检测以确保避免复发的夫妇的情况：他们获得适合移植的整倍体囊胚的概率是多少？
In an observational study, L Zhang et al. (2023b) saw a 30% rate of an aneuploid blastocyst in this group, substantially above the 21% rate of those presenting with no previous aneuploidy history.在一项观察性研究中，L Zhang等人（2023b）发现该组中非整倍体囊胚率为30%，显著高于无非整倍体病史组的21%。
These authors caution that these rates were derived from a population of women who were able to produce at least four blastocysts, and who had good ovarian reserve; hence they should be applied as risk estimates only to those in this same category.这些作者提醒，这些比率来自能够产生至少四个囊胚且卵巢储备良好的女性群体；因此，它们仅应作为风险估计应用于同一类别的群体。
Hook and Cross (1982) note the importance of distinguishing between the rate (which may be thought of as “past tense”) and the risk (which is “future tense”).Hook和Cross（1982）指出区分比率（可视为“过去时”）与风险（即“未来时”）的重要性。
They emphasize that although geneticists routinely extrapolate from rates in one population at one point in time, and may use these figures as risk estimates in another population and certainly at a later point in time, they should be on their guard for any evidence that a condition varies with time, geography,2 or ethnicity.他们强调，尽管遗传学家通常从一个群体在某一时间点的比率进行外推，并可能将这些数值用作另一群体（且肯定在更晚时间点）的风险估计，但他们应警惕任何表明某种状况随时间、地理或种族变化的证据。
But actually, there is little indication that any important variation exists.但实际上，几乎没有迹象表明存在任何重要变异。
Chromosomal biology appears to be rather consistent throughout the human race and across the centuries.染色体生物学似乎在整个人类种族中以及跨越数个世纪都相当一致。
Doing a Segregation Analysis Segregation analysis is essentially a simple exercise.进行分离分析分离分析本质上是一项简单的练习。
A farmer who surveys a flock of newborn lambs and notes that 3 are black and 97 are white has done a segregation analysis.一位农民检查一群新生羔羊，发现3只黑色、97只白色，这就是进行了一次分离分析。
In human cytogenetic segregation analysis, the exercise involves looking at a (preferably large) number of offspring of a particular category of parent: parents who carry some particular chromosome rearrangement, or those who have had a child with a chromosomal abnormality while they themselves are karyotypically normal.在人类细胞遗传学分离分析中，这项练习涉及观察某一特定类别父母（携带某种特定染色体重排的父母，或自身核型正常但曾生育染色体异常孩子的父母）的（最好是大批）后代。
The proportion of these parents’ children who are abnormal is noted (say, 3 out of 100), and this datum serves as the point estimate of the recurrence risk (thus, 3%).记录这些父母的孩子中异常的比例（例如，100个中有3个），该数据即作为复发风险的点估计值（因此为3%）。
Although segregation analysis is simple in principle, there are potential pitfalls in its application, the most important of which is ascertainment bias.尽管分离分析原理简单，但在应用中存在潜在陷阱，其中最重要的是确定偏倚。
We will deal with this problem only briefly.我们只会简要地处理这个问题。
It is important that the counselor know of ascertainment bias, and recognize whether it has been accounted for in the published works consulted.咨询师需了解确认偏误，并识别在查阅的已发表文献中是否已对其加以考虑。
But it is not necessary to understand the complex and sophisticated mechanics of segregation analysis in detail.但不必详细了解分离分析复杂而精妙的机制。
The reader wishing fuller instruction is referred to Murphy and Chase (1975), Emery (1986), and Stene and Stengel-Rutkowski (1988).希望获得更详细说明的读者，请参阅Murphy与Chase（1975）、Emery（1986）以及Stene与Stengel-Rutkowski（1988）的著作。
The classic example of ascertainment bias is that of the analysis of the sex ratio in sibships of military recruits in World War I.确认偏倚的经典例子是对第一次世界大战中入伍士兵的同胞性别比例分析。
Adding up the numbers of brothers and sisters, there was a marked excess of males.将兄弟姐妹的人数加起来，男性明显多于女性。
But of course (in 1914–1918) the recruit himself had to be male.当然（在1914–1918年间），新兵本人必须是男性。
Once he was excluded from the total in each sibship, the overall sex ratio was normal, namely 2 A curious difference in the types of chromosome abnormality from prenatal testing in different regions of China (J Zhang et al. 2023a) remains unexplained.一旦他从每个同胞群的总数中被排除，总体性别比例是正常的，即 2 中国不同地区产前检测中染色体异常类型的奇特差异（张杰等人，2023a）仍未得到解释。
41 DIFFERENT TYPES OF RISK FIGURE
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80 BASIC CONCEPTS 1.0.80 基本概念 1.0.
Likewise, in a cytogenetic segregation analysis, the individual whose abnormality brought the family to attention—the proband—is excluded from the calculation.同样，在细胞遗传学分离分析中，因异常而使该家庭受到关注的个体——即先证者——被排除在计算之外。
That person had to be abnormal.那个人一定不正常。
Furthermore, for very many classical chromosomal scenarios, that individual’s carrier parent, grandparent, and so on in a direct vertical line, had to be phenotypically normal to have been a parent.此外，对于许多经典染色体情况而言，该个体的携带者父母、祖父母等直系亲属在表型上必须正常，才能成为其父母。
These individuals must also be excluded from an analysis of their own sibship, if that generation is available for study.这些个体也必须被排除在对他们自身同胞群的分析之外，如果该世代可供研究的话。
Other sibships may be included in full.其他兄弟姐妹关系可能会被完整包括在内。
These manipulations—dropping the proband and the heterozygous direct-line antecedents—are the major steps to be taken to avoid the distorting effects of ascertainment bias.这些操作——剔除先证者及其杂合直系祖先——是避免确定偏倚扭曲效应的主要步骤。
Another potential methodological confounder for the aficionado is ascertainment probability.对于爱好者而言，另一个潜在的方法学混杂因素是确定概率。
For example, families with more affected members may be more likely to come to medical attention, which would unduly weight the data.有更多受影响成员的家庭可能更倾向于就医，这会使数据权重失衡。
There are means to overcome this problem.有办法克服这个问题。
Family/population studies on the microdeletions, microduplications, and copy number variants (CNVs) of 21st-century chromosomology present a more difficult problem.21世纪染色体学中关于微缺失、微重复和拷贝数变异（CNVs）的家系/群体研究提出了一个更为棘手的问题。
Non-penetrance and variable expressivity, and phenotypes confined to intellectual/behavioral traits and in some of mild degree, complicate the picture.非外显性和可变表达性，以及局限于智力/行为特征且部分程度较轻的表型，使情况复杂化。
Where is the threshold to be taken as affected/unaffected?阈值应如何界定为受影响/未受影响？
The pioneers in this field are Vassos et al. (2010) and Rosenfeld et al. (2013), who compared prevalences of CNVs in affected cohorts versus a presumed normal population.该领域的先驱是Vassos等人（2010年）和Rosenfeld等人（2013年），他们比较了受影响群体与假定正常人群中CNV的患病率。
The work of Vassos et al. was focused specifically on schizophrenia.Vassos等人的研究特别关注精神分裂症。
Goh et al. (2025) undertook a formal review of several published studies, calculating penetrance values for many CNVs, and these data are listed in Appendix C.Goh等人（2025年）对几项已发表的研究进行了正式综述，计算了许多CNV的外显率值，这些数据列于附录C中。
We discuss these conditions in Chapter 14 and Chapter 18.我们将在第14章和第18章讨论这些情况。
Essential to a good analysis is good data, or at least as good as possible.良好的分析关键在于良好的数据，或至少尽可能优质的数据。
Some retrospective information may be uncertain.某些回顾性信息可能不确定。
In a family translocation study, did a phenotypically abnormal great uncle who died as a child in 1930 have the “family aneuploidy”? (Old photos may be very helpful in this respect.) Some family skeletons may remain in cupboards unopened to the interviewer.在一项家族易位研究中，一位1930年童年夭折的表型异常叔祖父是否携带“家族非整倍体”？（老照片在这方面可能非常有帮助。）一些家族隐秘可能仍锁在柜中，对访谈者闭口不谈。
Particularly in the follow-up of prenatal diagnosis results, it is important to know the endpoint of data collection of the child and how the data were collected: at birth or until school age, by formal examination or by anecdotal report.特别是在产前诊断结果的随访中，了解儿童数据收集的终点以及数据收集方式至关重要：是在出生时还是到学龄期，是通过正式检查还是传闻报告。
The investigative zeal, clinical judgment, and personal qualities of the researcher are crucial in getting the right information, and getting it all.研究者的调查热情、临床判断和个人素质对于获取正确且完整的信息至关重要。
THE DERIVATION OF A “PRIVATE” RECURRENCE RISK FIGURE We will demonstrate some of the previously noted principles in estimating a private recurrence risk figure for the hypothetical family depicted in Figure 4–1.推导“个体化”复发风险值 我们将演示如何为图4-1中假设的家族估算个体化复发风险值，其中涉及前述的一些原则。
Six sibships are available for analysis: one in generation II, two in generation III, and three in generation IV.有六个同胞群可供分析：第二代一个，第三代两个，第四代三个。
We determine the segregation ratio in each.我们确定每个同胞群的分离比。
It is conventional to form a table with a row for each sibship, noting the numbers of phenotypically normal (carrier, non-carrier, unkaryotyped) and phenotypically abnormal offspring (Table 4–1).通常的做法是制作一个表格，每个同胞群占一行，记录表型正常（携带者、非携带者、未核型分析）和表型异常后代的数量（表4-1）。
The figures in parentheses give raw totals in these sibships, but then the proband (IV:4) and his heterozygous antecedents (II:1 and III:1) are excluded from their sibships.括号中的数字给出了这些同胞群的原始总数，但先证者（IV:4）及其杂合子祖先（II:1和III:1）被排除在其同胞群之外。
Note that I:1’s heterozygosity must be inferred from his wife’s and children’s karyotypes. (It is a subtle question whether his offspring should properly be included in the analysis, which we will not pursue here.) We see that the offspring of heterozygous parents total 14, the proband and the heterozygous antecedents having been excluded.注意，I:1的杂合性必须根据其妻子和子女的核型推断。（其子女是否应被纳入分析是一个微妙的问题，此处不深入探讨。）我们看到，杂合子父母的后代总数为14人，先证者和杂合子祖先已被排除。
The proportion of abnormal children is 3/14 (0.21).异常儿童的比例为3/14（0.21）。
This, then, is a point estimate of the risk for recurrence in a future pregnancy of a heterozygote.因此，这是杂合子未来妊娠复发风险的点估计值。
The reader should know intuitively Deriving and Using a Risk Figure 81 that an estimate based on just 14 children is not going to be very precise (but not to be discarded).读者应凭直觉知道，基于仅14名儿童的估计不会非常精确（但也不应舍弃）。
And what of children who had died before the family cytogenetic study was done?那么，在家族细胞遗传学研究完成之前已去世的儿童又该如何处理？
Let us suppose this was the case with III:4 and 5.假设这是III:4和5的情况。
If there was good historic evidence for their having been chromosomally abnormal, a better estimate would be 5/14 (0.36).如果有可靠的历史证据表明他们存在染色体异常，那么更准确的估计值将是5/14（0.36）。
VanDerwerken (2015) takes the sophistication of a “private” risk assessment to a further level, in applying the principles of Bayesian analysis.VanDerwerken（2015）将“私人”风险评估的复杂性提升到了更高层次，应用了贝叶斯分析的原则。
He proposes that a prior probability due to relevant literature data is usefully to be taken into account, and that this can fine-tune the accuracy of advice given.他提出，应充分考虑相关文献数据带来的先验概率，这可以微调所提供建议的准确性。
The mathematically sophisticated reader is referred to his paper.数学素养较高的读者可参阅他的论文。
Genetic Heterogeneity and the Use of Empiric Risk Data It is not necessarily valid to extrapolate from one family’s experience to a prediction for another.遗传异质性与经验风险数据的使用 将一个家庭的经验外推至对另一个家庭的预测并不一定有效。
Different factors may cause an abnormality in different families.不同家庭中可能导致异常的因素各不相同。
As an obvious example, it would be misleading to “lump” all Down syndrome families to determine Table 4–1.一个明显的例子是，将所有唐氏综合征家庭“混为一谈”来确定表4–1会产生误导。
Calculating a Recurrence Risk Due to a Familial Translocation PARENT OF SIBSHIP SIBSHIPS AFFECTED CARRIER NON-CARRIER UNKARYOTYPED TOTAL I:1 0 1 (2) 2 0 3 II:1 1 1 (2) 0 2 4 II:2 0 1 0 1 2 III:1 2 (3) 0 1 0 3 III:2 0 1 0 0 1 III:7 0 0 1 0 1 Total 3 4 4 3 14 Notes: These data come from the family shown in Figure 4–1.计算由家族性易位导致的再发风险 同胞的父母 同胞组 受影响 携带者 非携带者 未核型分析 总计 I:1 0 1 (2) 2 0 3 II:1 1 1 (2) 0 2 4 II:2 0 1 0 1 2 III:1 2 (3) 0 1 0 3 III:2 0 1 0 0 1 III:7 0 0 1 0 1 总计 3 4 4 3 14 注：这些数据来自图4–1所示的家庭。
The numbers in brackets refer to the raw totals, before the removal of the proband and the heterozygous antecedents.括号中的数字指的是在去除先证者和杂合子祖先之前的原始总数。
Figure 4–1.图4–1。
A Family Study.一项家庭研究。
Notes: Hypothetical pedigree in which a chromosomal rearrangement is segregating.注：假设的系谱图，其中存在染色体重排的分离。
Filled symbol, abnormal individual with unbalanced karyotype; half-filled symbol, balanced carrier; N in symbol = 46,N.填充符号，核型不平衡的异常个体；半填充符号，平衡携带者；符号中的N = 46,N。
The proband is, as is conventional, indicated by an arrow.先证者按惯例用箭头表示。
42 DIFFERENT TYPES OF RISK FIGURE
▶ 查看文稿（中英对照）
82 BASIC CONCEPTS a recurrence risk figure.82 基本概念 一个再发风险数值。
We need to “split” into the different karyotypic classes of standard trisomy, familial translocations, and de novo translocations.我们需要“细分”为不同的核型类别：标准三体、家族性易位和新发易位。
The standard trisomic category requires further splitting in terms of maternal age.标准三体类别需要根据母亲年龄进一步细分。
In a unique case, a woman had three trisomy 21 conceptions and displayed a tendency to produce multiple cells with differing (“variegated”) aneuploidies in at least skin, blood, and gonad (Fitzgerald et al. 1986).在一个罕见病例中，一名女性三次怀有21三体胎儿，并表现出至少在皮肤、血液和性腺中产生多种不同（“杂色”）非整倍体细胞的倾向（Fitzgerald et al. 1986）。
She required unique advice.她需要独特的建议。
And in reciprocal translocation families, uniqueness is the rule!而在相互易位家族中，独特性才是常态！
It is generally reasonable (and often all that is feasible or possible) to apply a risk figure derived from the study of families with a similar, albeit not exactly identical, chromosomal arrangement.通常合理（且往往是可行或可能做到的）的做法是，应用从具有相似（尽管并非完全相同）染色体排列的家族研究中得出的风险数值。
But occasionally a family is large enough for a “private” estimate of the recurrence risk to be made from the family itself.但偶尔，某个家族规模足够大，可以基于该家族自身进行“私人化”的复发风险评估。
This estimate, if it is precise enough (see the later discussion of confidence limits and standard error), is the most valid to offer that family.如果该评估足够精确（参见后文关于置信限和标准误的讨论），那么它就是能为该家族提供的最有效的评估。
Pregnancy Outcomes to which the Risk Figures Refer With particular reference to the situation of a parent heterozygous for a chromosomal rearrangement, risk figures are generally presented in terms of “the risk that a liveborn child would have a chromosome imbalance related to the parental translocation.” The numerator is the number of aneuploid babies, and the denominator is the number of all babies.风险数值所指的妊娠结局 特别针对染色体重排杂合子亲本的情况，风险数值通常以“活产子女出现与亲本易位相关的染色体失衡的风险”来表示。分子是非整倍体婴儿的数量，分母是所有婴儿的数量。
Thus, considering the example of the common t(11;22)(q23;q11) translocation (Chapter 5), Stengel-Rutkowski et al. (1988) accumulated data on a total of 318 births (the denominator) to carrier parents, of whom, after ascertainment correction, nine (the numerator) had the 47,+der(22) aneuploidy, and 9/318 gives the risk expressed as a percentage, 2.8%.因此，以常见的t(11;22)(q23;q11)易位（第5章）为例，Stengel-Rutkowski等人（1988）收集了携带者亲本总共318次分娩（分母）的数据，其中经过确认校正后，有9例（分子）为47,+der(22)非整倍体，9/318得出风险百分比为2.8%。
Separating out mothers and fathers, the respective risk figures are 3.7% (9/241) and <0.7% (0/77).将母亲和父亲分开统计，各自的风险数值分别为3.7%（9/241）和<0.7%（0/77）。
For those choosing prenatal diagnosis, the risk figure of interest relates to the timing of the procedure, generally chorionic villus sampling (usually done at 10–12 weeks) and amniocentesis (15–17 weeks).对于选择产前诊断的人，他们关心的风险数值与操作时间有关，通常是绒毛膜取样（通常在10-12周进行）和羊膜穿刺术（15-17周）。
In other words, they want to know how likely it is they will have to face the actuality of a decision about termination.换句话说，他们想知道自己需要面对终止妊娠决定这一现实的可能性有多大。
The risk here is likely to be higher (7% in the case of the 11;22 translocation), given that some of the abnormal pregnancies would have spontaneously aborted some time after that period of gestation.这里的风险可能更高（在11;22易位的情况下为7%），因为部分异常妊娠会在该孕周之后某个时间自然流产。
Table 4–2 sets out these and other possible ways of considering risk.表4-2列出了这些以及其他可能的风险考量方式。
Table 4–2.表4-2。
Different Ways of Looking at the Quantum of Reproductive Risk Due to a Parent Being a Carrier of a Chromosomal Rearrangement NUMERATOR DENOMINATOR Abnormal liveborn baby All liveborns Abnormal liveborn baby All recognized pregnancies Abnormal amniocentesis result (early second trimester) All pregnancies at ~16 weeks 8–14 week miscarriage All recognized pregnancies Abnormal embryo on biopsy All embryos from one in vitro fertilization procedure Deriving and Using a Risk Figure 83 Association: Coincidental or Causal?因亲本为染色体重排携带者所致生殖风险量的不同考量方式 分子 分母 异常活产婴儿 所有活产儿 异常活产婴儿 所有确认妊娠 异常羊膜穿刺结果（孕早期末） 约16周的所有妊娠 8-14周流产 所有确认妊娠 活检异常胚胎 一次体外受精程序中的所有胚胎 推导与使用风险数值 83 关联：巧合还是因果？
The counselor not infrequently encounters the problem of a chromosomal “abnormality” discovered in a phenotypically abnormal individual but in whose family, others—who are quite normal—are then shown to have, apparently, exactly the same rearrangement.咨询师经常遇到这样的问题：在一个表型异常个体中发现染色体“异常”，但其家族中其他完全正常的人随后被证明显然具有完全相同的重排。
Does a genetic risk apply, then, to children of the carrier, to whom the same rearranged chromosome may be transmitted?那么，遗传风险是否适用于携带者的子女，因为相同的重排染色体可能遗传给他们？
From classical cytogenetics, the familial paracentric inversion is a good example.从经典细胞遗传学来看，家族性臂内倒位是一个很好的例子。
In a review of 69 probands, Price et al. (1987) list the phenotypic abnormalities that led to these individuals coming to a chromosome study.在对69名先证者的回顾中，Price等人（1987）列出了导致这些个体接受染色体研究的表型异常。
There was a collection of various clinical indications, with no consistent pattern (other than that intellectual disability was frequent), and several ascertained quite by chance at prenatal diagnosis.这些异常包括各种临床指征，没有一致的模式（除了智力障碍较为常见），并且有几例是在产前诊断中完全偶然发现的。
By definition, one parent carries the same inversion; and if the net is widened, often other relatives do so as well (Groupe de Cytogénéticiens Français 1986a).根据定义，一位亲本携带相同的倒位；若扩大筛查范围，通常其他亲属也会如此（法国细胞遗传学家小组 1986a）。
In this context, and provided of course that the carrier relatives are phenotypically normal, one would reach the conclusion that the chromosome rearrangement was balanced, with no functional compromise of the genome, and that it was coincidence that led to its discovery (Romain et al. 1983).在此背景下，且假设携带者亲属表型正常，则可得出结论：该染色体重排是平衡的，未对基因组功能造成损害，其被发现纯属偶然（Romain 等，1983）。
But when some very unusual clinical picture is associated with a paracentric inversion that is rare or previously undescribed (as many inversions are), some writers are skeptical of coincidence and propose a causal link (Fryns et al. 1994; Urioste et al. 1994).但当某种非常罕见的临床表现与一种少见或此前未被描述过的臂内倒位（许多倒位情况如此）相关联时，一些研究者对巧合持怀疑态度，并提出存在因果联系（Fryns 等，1994；Urioste 等，1994）。
Similarly, Wenger et al. (1995), noting the coincidence of children with an apparently balanced familial translocation and being phenotypically abnormal, wrote that “the chance that two rare events in the same individual are unrelated seems unlikely to us.” Here, there is a risk of deception due to “Kouska’s fallacy”—Kouska was a fictional 19th-century philosopher who concluded that the combination of unlikely events that led to his parents meeting was too implausible to believe, and that therefore he himself could not exist (Lubinsky 1986).同样，Wenger等人（1995）注意到，携带看似平衡的家族性易位且表型异常的儿童具有巧合性，并写道：“同一人身上发生两件罕见事件且彼此无关的可能性，在我们看来似乎不大。”此处存在因“库斯卡谬误”而导致的误导风险——库斯卡是19世纪虚构的哲学家，他得出结论认为，导致其父母相遇的一系列不太可能事件的组合过于难以置信，因此他自己不可能存在（Lubinsky 1986）。
As does Lubinsky, we must insist on the point: The proband had to be phenotypically abnormal, and the coexistence of a subsequently discovered different abnormal event (the karyotype) need not be seen as necessarily remarkable. (Having made that point, we cannot, nevertheless, discount the alternative interpretation that these authors may indeed have concluded correctly.) A similar question arises when two rare karyotypes are seen in the same family, or when one individual has more than one aneuploidy.正如卢宾斯基所言，我们必须坚持这一点：先证者必须在表型上异常，而随后发现的不同异常事件（核型）与之共存，未必需要被视为显著异常。（尽管提出了这一点，但我们仍不能忽视另一种解释，即这些作者可能确实得出了正确的结论。）当同一家族中出现两种罕见核型，或同一个体存在多种非整倍体时，也会出现类似的问题。
A double aneuploidy such as Klinefelter plus Down syndrome, 48,XXY,+21, could be interpreted as two separately arising nondisjunctions but with each occurring on the basis of the same underlying predisposing factor (such as maternal age).一个双非整倍体，如克兰费尔特综合征合并唐氏综合征（48,XXY,+21），可解释为两次分别发生的染色体不分离，但每次均基于相同的潜在易感因素（如母亲年龄）。
The two conditions occur together more often than the product of the frequency of each singly, which would be consistent with that interpretation.这两个条件同时出现的频率高于各自单独出现频率的乘积，这与上述解释一致。
Alternatively, if the XXY component could be shown to reflect a paternal meiotic error, while the trisomy 21 was of maternal origin, then the association could be seen as coincidental.如果XXY成分能被证明反映父方减数分裂错误，而21三体源于母方，那么这种关联可被视为巧合。
Two different types of abnormality, such as Klinefelter plus Prader-Willi syndrome (a handful of cases of which have been published; see Nowaczyk et al. 2004), might also be judged to reflect two unrelated abnormal events, at least for the deletional form of Prader-Willi syndrome, given that the mechanisms leading to nondisjunction and to deletion are quite different.两种不同类型的异常，例如克莱恩费尔特综合征合并普拉德-威利综合征（已有少数病例报道；参见Nowaczyk等，2004），也可能被视为反映了两个不相关的异常事件，至少对于普拉德-威利综合征的缺失型而言，因为导致不分离和缺失的机制截然不同。
The prior probability of two abnormal karyotypes coinciding might be a very small figure (1/2000 × 1/15,000 = 1/30,000,000 in the foregoing example); but recalling that the range of abnormal karyotypes is very wide, it should not necessarily be seen as reflecting some extraordinary predisposition when two两种异常核型同时出现的先验概率可能是一个非常小的数字（在前述例子中为1/2000 × 1/15,000 = 1/30,000,000）；但考虑到异常核型的范围非常广泛，当两种异常核型同时出现时，不应必然将其视为反映了某种特殊的易感性。
43 PRESENTATION OF A RISK FIGURE
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84 BASIC CONCEPTS abnormalities are diagnosed in the one individual or family.84 基本概念 异常情况是在同一个体或家族中被诊断出来的。
Coincidences do happen, and interesting coincidences are publishable (Schneider et al. 2004).巧合确实会发生，而有趣的巧合是可以发表的（Schneider 等，2004）。
In the molecular era, the matter of CNVs brings the question of causality into a sharp focus, although some of the answers may be less than sharp.在分子时代，拷贝数变异的问题将因果关系的议题推向了聚光灯下，尽管部分答案可能并不那么清晰。
A small molecular duplication, for example, which might at first sight appear to be a plausible candidate as explanation for a child’s abnormal phenotype, may be judged less likely as culpable if the same observation is made on the DNA sample from a parent.例如，一个最初看似可以合理解释儿童异常表型的小分子重复，如果在父母的DNA样本中也观察到相同情况，则其作为致病原因的可能性就会降低。
And yet, in the complexity that CNVs present, there may yet remain a possibility that such a duplication could contribute to abnormality when existing on a different genetic background.然而，在CNVs所呈现的复杂性中，当这种重复存在于不同的遗传背景上时，仍有可能导致异常。
In other words, and as discussed above, a particular CNV may be nonpenetrant in a parent but penetrant in the child—a concept that hitherto has had little relevance in clinical cytogenetics.换句话说，正如上文所述，特定的拷贝数变异（CNV）可能在父母中不表现，但在子女中表现——这一概念迄今在临床细胞遗传学中几乎没有相关性。
We can expect that CNV associations and their causing, or not, of abnormality will continue to be an active area of study (and see Chapter 18, Chapter 25, and Appendix C).我们可以预期，CNV关联及其是否导致异常将继续是一个活跃的研究领域（另见第18章、第25章和附录C）。
PRESENTATION OF A RISK FIGURE A risk figure is a probability statement, and it should be presented as such to the counselee in everyday language—for example, “There is a 50/50 chance for such and such an event,” and “The risk for such and such to happen is around one chance in 10.” The raw probability figure may not of itself be sufficient, and it is a test of the counselor’s skill to interpret figures so as to provide empathic guidance rather than presumptuous direction.呈现风险数据时，风险数据是一种概率表述，应以日常语言向咨询者呈现——例如，“某事件发生的概率是五五开”，以及“某情况发生的风险约为十分之一”。原始概率数据本身可能并不足够，而如何解读数据以提供共情式引导而非武断式指示，正是对咨询师专业能力的考验。
Loaded interpretative comments such as “The risk is quite high that . . .” or “There is only a small chance that . . .” should be used with great care.诸如“风险相当高……”或“可能性很小……”这类带有主观解读色彩的评论，应谨慎使用。
The perception of a risk figure as high or low may vary greatly according to an individual’s personality and life experiences, and the way he or she uses the language of numbers; the very act of discussing the risk may help the client see it in a less threatening light (Kessler and Levine 1987).对风险数值高低的感知可能因个体的性格、生活经历以及其使用数字语言的方式而存在巨大差异；讨论风险这一行为本身或许有助于客户以更少威胁性的视角看待风险（Kessler and Levine 1987）。
Some counselors use diagrams with cartoons showing a crowd of 100 people, with the risk fraction shown in a different color.一些咨询师使用带有卡通人物的图表，展示100人的人群，其中风险比例用不同颜色标出。
Dealing with risk advice in a pregnancy, in particular, can be anxiety-inducing.处理孕期风险建议，尤其可能引发焦虑。
Nagle et al. (2009) examined the views of 294 Australian mothers in the postpartum period and recorded preferences for how these women felt, in retrospect, that a risk of having a child with Down syndrome might best have been conveyed.Nagle等人（2009）调查了294名澳大利亚产后母亲的看法，并记录了她们回顾性认为的最佳传达生育唐氏综合征患儿风险的方式偏好。
The choices were as follows, with the fractions of the women choosing each category shown: 1.选择如下，各选项被女性选择的比例如下：
As a number in percentage, such as “1%” or “0.05%” 13% 2.作为百分比数字，例如“1%”或“0.05%” 13% 2.
In words such as “no increased risk” or “increased risk” 13% 3.无增加风险”或“增加风险”这类表述中，13% 3.
As numbers such as “1 in 10” or “1 in 1000” 37% 4.As numbers such as “1 in 10” or “1 in 1000” 37% 4.
In words such as “high risk” or “low risk” 19% 5.在“高风险”或“低风险”等词语中 19% 5%
Other (please specify) 0% A combination of the above 18% None of these stood out as an obvious best to help the counselor decide on the most appropriate approach.其他（请注明）0% 上述组合 18% 这些选项中没有哪一个明显是最佳选择，能够帮助咨询师决定最合适的方法。
People are different!人各有不同！
And people can see the same risk from different positions.而人们可以从不同的立场看到同样的风险。
For example, older women having an increased age-related risk (say, 1 in 100) for a child with Down syndrome may decide against an amniocentesis if a screening test gives a risk (say, 1 in 200) that年龄较大的女性，其生育患有唐氏综合征子女的年龄相关风险增加（例如，1/100），如果筛查测试给出的风险较低（例如，1/200），则可能决定不进行羊膜穿刺术。
44 PRECISION OF THE RISK FIGURE
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Deriving and Using a Risk Figure 85 is above the cut-off for access to amniocentesis (1 in 250) but lower than their “starting figure”; whereas a younger woman with an age-related risk of, for example, 1 in 500 is likely to opt for amniocentesis if she were to have the same 1 in 200 result from the screening test (Beekhuis et al. 1994).推导并使用风险数值 85高于接受羊膜穿刺术的临界值（1/250），但低于其“起始数值”；而一位年龄相关风险为1/500的年轻女性，若筛查结果同样为1/200，则很可能选择羊膜穿刺术（Beekhuis等，1994）。
Responses to risk figures might not always be what we, as scientifically trained professionals, would necessarily consider objective.对风险数据的回应可能并不总是我们这些受过科学训练的专业人士所认为的客观结果。
This is in the nature of the human condition!这就是人类境况的本质！
Urquhart (2016), a folklorist, gives her own perspective on the counseling she received during the course of prenatal diagnosis (in this case not for a chromosome condition, but rather for a Mendelian disorder, albinism).厄克特（2016）是一位民俗学家，她对自己在产前诊断过程中（此案例并非针对染色体异常，而是针对一种孟德尔遗传病——白化病）所接受的咨询提出了自己的见解。
She had “always had an insatiable urge to know the future.她“一直有一种无法满足的渴望，想要预知未来。
Coupled with a keen interest in the supernatural—as a folklore scholar and as a layperson—this has led me to forms of soothsaying like tarot cards and runes but also to the people who trade in clairvoyance.” When she was about to hear the results of her amniocentesis test, she writes, “First, she [the counselor] tells me the odds.作为一名民俗学者和普通爱好者，我对超自然现象怀有浓厚兴趣——这让我接触了塔罗牌、符文等占卜形式，也结识了从事通灵交易的人。”当她即将听到羊膜穿刺结果时，她写道：“首先，她（咨询师）告诉我概率。
But the numbers never meant anything to me.但这些数字对我毫无意义。
I put as much faith in those predictions as I might in a palm reading.我对这些预测的信任程度，与我看手相时差不多。
This child will either have albinism, or he will not.” In the event—to her initial consternation, but then fierce acceptance—he did not.这个孩子要么患有白化病，要么没有。”结果——起初她惊愕不已，但随后便坦然接受——孩子没有患病。
PRECISION OF THE RISK FIGURE As noted above, theoretical risk figures are true, and empiric risk figures are estimates; the former are exact, and the latter are not.风险数值的精确性 如上所述，理论风险数值是准确的，而经验风险数值是估算值；前者精确，后者不精确。
For an empiric figure we have a point estimate (e.g., 10%) and a likely range (e.g., 5%–15%) of where the risk actually is.对于经验数值，我们有一个点估计值（例如10%）和一个可能范围（例如5%–15%）来表明风险实际所在。
The more data that have been gathered, the more accurate the estimate and the narrower the likely range—and the more confidently, therefore, can the counselor present the figure.收集的数据越多，估算越准确，可能范围越窄——因此咨询师在呈现数值时也越有把握。
The likely range can be measured in different ways.可能范围可以通过不同方式衡量。
The standard error, which formally measures the precision of the estimate, can be used to give a sense of the region within which the true risk can realistically be considered to lie.标准误差正式衡量估算的精确性，可用于提示真实风险可能存在的合理区间。
The 95% confidence limits define the broad range that very probably (p = 0.95) encompasses the true risk.95%置信区间定义了一个宽泛范围，极有可能（p = 0.95）包含真实风险。