Part 3

PART 3: Chromosomal and Genomic Basis of Disease

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Ch6 — The Chromosomal and Genomic Basis of Disease (29)

The Chromosomal and Genomic Basis of Disease

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The Chromosomal and Genomic Basis of Disease Disorders of the Autosomes and Sex Chromosomes Feyza Yilmaz In this chapter…
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The Chromosomal and Genomic Basis of Disease Disorders of the Autosomes and Sex Chromosomes Feyza Yilmaz In this chapter we present several of the most common and best understood chromosomal and genomic disorders encountered in clinical practice, building on the general principles of clinical cytogenetics and genome analysis introduced in the previous chapter.疾病的染色体和基因组基础：常染色体和性染色体疾病 Feyza Yilmaz 在本章中，我们基于前一章介绍的临床细胞遗传学和基因组分析的一般原则，介绍临床实践中遇到的几种最常见且最明了的染色体和基因组疾病。
Each of the ­disorders presented here illustrates the principles of ­dosage ­balance and imbalance at the level of chromosomes and subchromosomal regions of the genome.这里介绍的每一种疾病都阐明了染色体和基因组亚染色体区域水平的剂量平衡与不平衡原则。
Because a wide range of phenotypes seen in clinical medicine involves chromosome and subchromosomal variants, we include in this chapter the spectrum of disorders that are characterized by intellectual disability or by abnormal or ambiguous sexual development.由于临床医学中观察到的广泛表型涉及染色体和亚染色体变异，我们在本章中包含了以智力残疾或异常或模糊的性发育为特征的一系列疾病。
Although many such disorders can be determined by single genes, the clinical approach to evaluation of such phenotypes frequently includes detailed chromosome and genome analysis.尽管许多此类疾病可由单基因决定，但评估这些表型的临床方法通常包括详细的染色体和基因组分析。
MECHANISMS OF ABNORMALITIES In this section we consider abnormalities that illustrate the major chromosomal and genomic mechanisms that underlie genetic imbalance of entire chromosomes or chromosomal regions.异常机制 在本节中，我们考虑那些说明整个染色体或染色体区域遗传不平衡的主要染色体和基因组机制的异常。
Overall, we distinguish four ­different categories of such abnormalities, each of which can lead to disorders of clinical significance: Disorders due to abnormal chromosome segregation (nondisjunction) Disorders due to recurrent and nonrecurrent chromosomal rearrangements, involving deletions or duplications at genomic hot spots Disorders due to unbalanced familial chromosomal abnormalities Disorders due to chromosomal and genomic events that reveal regions of genomic imprinting The distinguishing features of the underlying mechanisms are summarized in Although the categories of defects that result from these mechanisms can involve any chromosomes, we introduce them here in the context of autosomal abnormalities.总体而言，我们区分了四类不同的此类异常，每一类都可能导致临床上有意义的疾病：由异常染色体分离（不分离）引起的疾病；由复发性和非复发性染色体重排引起的疾病，涉及基因组热点区域的缺失或重复；由不平衡的家族性染色体异常引起的疾病；由揭示基因组印记区域的染色体和基因组事件引起的疾病。尽管这些机制导致的缺陷类别可能涉及任何染色体，但我们在此以常染色体异常为背景进行介绍。
WHOLE CHROMOSOME ANEUPLOIDY The most common variant in the human genome involves errors in chromosome segregation, typically leading to production of an abnormal gamete that has two copies or no copies of the chromosome involved in the nondisjunction event.整染色体非整倍体 人类基因组中最常见的变异涉及染色体分离错误，通常导致产生一个异常配子，该配子具有参与不分离事件的染色体的两个拷贝或零拷贝。
Notwithstanding the high frequency of such errors in meiosis and, to a lesser extent, in mitosis, there are only three well-defined nonmosaic chromosome disorders compatible with postnatal survival in which there is an abnormal dose of an entire autosome: trisomy 21 (Down syndrome), trisomy 18, and trisomy 13.尽管此类错误在减数分裂中发生频率很高，在有丝分裂中较低，但只有三种明确的非嵌合染色体疾病与出生后存活相容，其中整个常染色体剂量异常：21三体（唐氏综合征）、18三体和13三体。
It is surely no coincidence that these chromosomes are the ones with the smallest number of genes among all autosomes .这些染色体是所有常染色体中基因数量最少的，这绝非巧合。
The imbalance for more gene-rich chromosomes is presumably incompatible with long-term survival, and aneuploidy for some of these is frequently associated with pregnancy loss (see Each of these autosomal trisomies is associated with growth retardation, intellectual disability, and multiple congenital anomalies ( Nevertheless, each has a fairly distinctive phenotype that is immediately recognizable to an astute clinician in the newborn nursery.基因更丰富的染色体不平衡可能不利于长期存活，其中一些染色体的非整倍体常与妊娠丢失相关（见……）。这些常染色体三体中的每一种都与生长迟缓、智力残疾和多种先天性异常相关（见……）。尽管如此，每一种都有相当独特的表型，敏锐的临床医生在新生儿病房中可以立即识别。
Trisomies 18 and 13 are both less common than trisomy 21; survival beyond the first year is rare, in contrast to Down syndrome, in which the average life expectancy is over 50 years of age.18三体和13三体都比21三体少见；与唐氏综合征（平均预期寿命超过50岁）相比，生存超过第一年很少见。
The developmental abnormalities characteristic of any one trisomic state must be determined by the extra dosage of the particular genes on the additional chromosome.任何一种三体状态的特征性发育异常必定由额外染色体上特定基因的额外剂量决定。
Knowledge of the specific relationship between the extra chromosome and the consequent developmental abnormality has been limited to date.迄今为止，对额外染色体与其导致的发育异常之间特定关系的了解仍然有限。
Current research, however, is beginning to ­localize ­specific genes on the extra chromosome that are responsible for specific aspects of the abnormal ­phenotype, through direct or indirect modulation of patterning events during early development (see Chapter 15).然而，当前的研究开始定位额外染色体上通过直接或间接调节早期发育过程中的模式形成事件而导致异常表型特定方面的特定基因（见第15章）。
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principles of gene dosage and the likely role of imbalance for individual genes that underlie specific developmental asp…
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principles of gene dosage and the likely role of imbalance for individual genes that underlie specific developmental aspects of the phenotype apply to all aneuploid conditions; these are illustrated here in the context of Down syndrome, whereas the other conditions are summarized in Down Syndrome Down syndrome is by far the most common and best known of the chromosome disorders and is the single most common genetic cause of moderate intellectual disability.基因剂量原理以及个别基因失衡在表型特定发育方面可能发挥的作用适用于所有非整倍体状态；此处以唐氏综合征为例说明，而其他情况则在唐氏综合征中总结。唐氏综合征是目前最常见且最为人所知的染色体疾病，也是中度智力障碍最常见的单一遗传原因。
The population incidence of Down syndrome (see At ~30 years of age, the risk begins to rise sharply, approaching 1 in 10 births in the oldest maternal age group .唐氏综合征的人群发病率（参见：约30岁时，风险开始急剧上升，在最高龄产妇年龄组中接近1/10）。
Even though younger mothers have a much lower risk, their birth rate is much higher, and therefore more than half of the mothers of all newborns with Down syndrome are younger than 35 years.尽管年轻母亲的风险低得多，但其生育率却高得多，因此所有唐氏综合征新生儿的母亲中超过一半年龄小于35岁。
Down syndrome can usually be diagnosed at birth or shortly thereafter by its characteristic features, which vary among patients but nevertheless produce a distinctive phenotype .唐氏综合征通常可在出生时或出生后不久根据其特征性表现诊断，这些表现在患者间存在差异，但仍构成独特的表型。
Hypotonia may be the first abnormality noticed in the newborn.肌张力减退可能是新生儿中最早被注意到的异常。
In addition to characteristic dysmorphic facial features , the patients are short in stature and have brachycephaly with a flat occiput.除了特征性的面部畸形特征外，患者身材矮小，具有短头畸形和后枕扁平。
The neck is short, with loose skin on the nape.颈部短，项部皮肤松弛。
The hands are short and broad, often with a single transverse palmar crease and incurved fifth digits (termed fifth finger clinodactyly).手短而宽，常伴有单一掌横纹和第五指弯曲（称为第五指弯曲畸形）。
A major cause for concern in Down syndrome is intellectual disability.唐氏综合征中一个主要的关注点是智力障碍。
Even though in early infancy the child may not seem delayed in development, the delay is usually obvious by the end of the first year.尽管在婴儿早期孩子可能看似发育无延迟，但到第一年末发育迟缓通常变得明显。
Although the extent of intellectual disability varies among individuals from moderate to mild, many children with Down syndrome develop into interactive and even self-reliant persons, and most attend local schools.尽管智力障碍程度从中度到轻度不等，但许多唐氏综合征儿童能成长为善于交际甚至自立的人，并且大多数就读于当地学校。
There is a high degree of variability in the phenotype of Down syndrome individuals; specific abnormalities are detected in almost all patients, but others are seen only in a subset of cases.唐氏综合征个体的表型具有高度变异性；几乎所有患者均可检测到特定异常，但其他异常仅见于部分病例。
Congenital heart disease is present in about half of all liveborn infants with Down syndrome.约一半的唐氏综合征活产婴儿患有先天性心脏病。
Certain malformations, such as duodenal atresia and tracheoesophageal fistula, are much more common in Down syndrome than in other disorders..某些畸形，如十二指肠闭锁和气管食管瘘，在唐氏综合征中比其他疾病中更为常见。
Features of Autosomal Trisomies Compatible with Postnatal Survival Feature Trisomy 21 Trisomy 18 Trisomy 13 Incidence (live births) 1 in 700 1 in 6000–8000 1 in 5000–15,000 Clinical presentation Hypotonia, short stature, loose skin on nape, single palmar crease, clinodactyly Hypertonia, prenatal growth deficiency, characteristic fist clench, rocker-bottom feet Microcephaly, sloping forehead, characteristic fist clench, rockerbottom feet, polydactyly Dysmorphic facial features Flat occiput, epicanthal folds, upslanting palpebral fissures Receding jaw, low-set ears Ocular abnormalities, cleft lip and palate Intellectual disability Moderate to mild Severe Severe Other common features Congenital heart disease Severe heart malformations Severe CNS malformations Duodenal atresia Feeding difficulties Congenital heart defects Risk for leukemia Risk for premature dementia Life expectancy 60 yr Typically less than a few months; almost all &lt;1 yr 50% die within first month, &gt;90% within first year CNS, Central nervous system.可存活至出生后的常染色体三体综合征特征：21三体、18三体、13三体；发病率（活产）分别为1/700、1/6000–8000、1/5000–15,000；临床表现：21三体为肌张力减退、身材矮小、项部皮肤松弛、单一掌横纹、第五指弯曲畸形；18三体为肌张力增高、产前生长不足、特征性握拳、摇椅底足；13三体为小头畸形、前额倾斜、特征性握拳、摇椅底足、多指（趾）畸形；面部畸形特征：21三体为后枕扁平、内眦赘皮、上斜睑裂；18三体为下颌后缩、低位耳；13三体为眼部异常、唇腭裂；智力障碍：21三体为中度至轻度，18和13三体为重度；其他常见特征：21三体有先天性心脏病、十二指肠闭锁、白血病风险、早发性痴呆风险，预期寿命60年；18三体有严重心脏畸形、喂养困难，预期寿命通常不足数月，几乎全部<1年；13三体有严重中枢神经系统畸形、先天性心脏缺陷，50%在第一个月内死亡，>90%在第一年内死亡。CNS即中枢神经系统。
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 81 Only ~20% to 25% of trisomy 21 conceptuses survive to birth (see Among D…
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 81 Only ~20% to 25% of trisomy 21 conceptuses survive to birth (see Among Down syndrome conceptuses, those least likely to survive are those with congenital heart disease; approximately one-fourth of the liveborn infants with heart defects die before their first birthday.疾病的染色体与基因组基础 81 仅约20%至25%的21三体受精卵能存活至出生（在唐氏综合征受精卵中，最不可能存活的是那些患有先天性心脏病的；在活产婴儿中，约四分之一有心脏缺陷的婴儿在一岁前死亡）。
There is a 15-fold increase in the risk for leukemia among individuals with Down syndrome who survive the neonatal period.存活过新生儿期的唐氏综合征患者患白血病的风险增加15倍。
Premature dementia, associated with the neuropathologic findings characteristic of Alzheimer disease (cortical atrophy, ventricular dilatation, and neurofibrillary tangles), affects nearly all individuals with Down syndrome several decades earlier than the typical age at onset of Alzheimer disease in the general population.早发性痴呆，伴随阿尔茨海默病的特征性神经病理学发现（皮质萎缩、脑室扩张和神经原纤维缠结），影响几乎所有唐氏综合征患者，且发病年龄比普通人群阿尔茨海默病典型发病年龄早数十年。
As a general principle it is important to think of this constellation of clinical findings, their variation, and likely outcomes in terms of gene imbalance—the relative overabundance of specific gene products; their impact on various critical pathways in particular tissues and cell types, both early in development and throughout life; and the particular alleles present in an individual’s genome, both for genes on the trisomic chromosome and for the many other genes inherited from the parents.作为一般原则，重要的是从基因失衡的角度思考这一组临床表现、其变异和可能的结局——特定基因产物的相对过量；这些产物在发育早期及整个生命过程中对特定组织和细胞类型中各种关键通路的影响；以及个体基因组中存在的特定等位基因，既包括三体染色体上的基因，也包括从父母遗传的许多其他基因。
The Chromosomes in Down Syndrome The clinical diagnosis of Down syndrome usually presents no particular difficulty.唐氏综合征的染色体 唐氏综合征的临床诊断通常没有特别困难。
Nevertheless, karyotyping is necessary for confirmation and to provide a basis for genetic counseling.然而，核型分析对于确诊和提供遗传咨询的基础是必要的。
Although the specific abnormal karyotype responsible for Down syndrome usually has little effect on the phenotype of the patient, it is essential for determining the recurrence risk. 20 22 24 26 28 30 32 34 36 Cases Controls Population 1990 1992 1994 1996 Birthyear Mean Maternal Age 1998 2000 2002 2004 2006 Comparison of mean maternal ages at the time of birth.尽管导致唐氏综合征的特定异常核型通常对患者表型影响不大，但它对于确定复发风险至关重要。20 22 24 26 28 30 32 34 36 病例 对照 人群 1990 1992 1994 1996 出生年份 平均母亲年龄 1998 2000 2002 2004 2006 出生时平均母亲年龄的比较。
Case (top): maternal age at birth of infant with trisomy 21; control: maternal age at birth of infant without trisomy 21; population: maternal ages at birth of infants in the population from cases and controls.病例（上方）：21三体婴儿出生时的母亲年龄；对照：非21三体婴儿出生时的母亲年龄；人群：来自病例和对照的人群中婴儿出生时的母亲年龄。
(Data from Allen EG, Freeman SB, Druschel C, et al: Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects, Hum Genet 125:41–52, 2009; Bull MJ: Down syndrome, NEJM 382:2344–2352, 2020.) Kayla is representing the National Down Syndrome Society (ndss. org).（数据来自Allen EG, Freeman SB, Druschel C等：母亲年龄与染色体不分离起源评估的21三体风险：亚特兰大和全国唐氏综合征项目报告，Hum Genet 125:41–52, 2009；Bull MJ：唐氏综合征，NEJM 382:2344–2352, 2020。）Kayla代表全国唐氏综合征协会（ndss.org）。
Her hand of greeting shows characteristic short fingers; other typical features include her flattened nasal bridge, small low-set ears, and eyes displaying epicanthal folds and upslanting palpebral fissures.她打招呼的手显示出特征性的短指；其他典型特征包括扁平的鼻梁、小而低位耳、以及显示内眦赘皮和上斜睑裂的眼睛。
(Photograph by Rick Guidotti, Positive Exposure, www. positiveexposure. org.)（摄影：Rick Guidotti，Positive Exposure，www.positiveexposure.org。）
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Trisomy 21.
Ch6 — Segment 4
Trisomy 21.21三体。
In at least 95% of all patients, the Down syndrome karyotype has 47 chromosomes, with an extra copy of chromosome 21 .在至少95%的患者中，唐氏综合征的核型有47条染色体，其中多了一条21号染色体。
This trisomy results from meiotic nondisjunction of the chromosome 21 pair.这种三体是由21号染色体对在减数分裂中不分离造成的。
As noted earlier, the risk for having a child with trisomy 21 increases with maternal age, especially after the age of 30 years .如前所述，生育21三体患儿的风险随母亲年龄增加而增加，尤其是在30岁以后。
The meiotic error responsible for the trisomy usually occurs during maternal meiosis (~90% of cases), predominantly in meiosis I, but ~10% of cases occur in paternal meiosis, often in meiosis II.导致三体的减数分裂错误通常发生在母方减数分裂（约90%的病例），主要发生在减数第一次分裂，但约10%的病例发生在父方减数分裂，常在减数第二次分裂。
Typical trisomy 21 is a sporadic event, and thus recurrences are infrequent, as will be further discussed later in this chapter.典型的21三体是偶发事件，因此复发不常见，本章稍后将进一步讨论。
Approximately 2% of Down syndrome patients are mosaic for two cell populations – one with a normal karyotype and one with a trisomy 21 karyotype.大约2%的唐氏综合征患者为两种细胞群体的嵌合体——一种具有正常核型，另一种具有21三体核型。
The phenotype may be milder than that of typical trisomy 21, but there is wide variability in phenotypes among mosaic patients, presumably reflecting the variable proportion of trisomy 21 cells in the embryo during early development.表型可能比典型的21三体更轻，但嵌合体患者表型变异很大，可能反映了胚胎早期发育中21三体细胞比例的变化。
Robertsonian Translocation.罗伯逊易位。
Approximately 4% of Down syndrome patients have 46 chromosomes, one of which is a Robertsonian translocation between chromosome 21q and the long arm of one of the other acrocentric chromosomes (usually chromosome 14 or 22) .大约4%的唐氏综合征患者有46条染色体，其中一条是21q与另一个近端着丝粒染色体（通常是14号或22号染色体）长臂之间的罗伯逊易位。
The translocation chromosome replaces one of the normal acrocentric chromosomes, and the karyotype of a Down syndrome patient with a Robertsonian translocation between chromosomes 14 and 21 is therefore 46,XX or XY,rob(14;21)(q 10;q 10),+21 (see Despite having 46 chromosomes, patients with a Robertsonian translocation involving chromosome 21 are trisomic for genes on the entirety of 21q.易位染色体取代了一个正常的近端着丝粒染色体，因此，具有14号和21号染色体之间罗伯逊易位的唐氏综合征患者的核型为46,XX或XY,rob(14;21)(q10;q10),+21（参见尽管有46条染色体，涉及21号染色体的罗伯逊易位患者在整个21q上的基因为三体）。
A carrier of a Robertsonian translocation, involving, for example, chromosomes 14 and 21, has only 45 chromosomes; one chromosome 14 and one chromosome 21 are missing and are replaced by the translocation chromosome.例如，涉及14号和21号染色体的罗伯逊易位携带者只有45条染色体；缺失了一条14号染色体和一条21号染色体，并被易位染色体取代。
The gametes that can be formed by such a carrier are shown in for recurrence, and thus prenatal diagnosis should be considered in any subsequent pregnancy.此类携带者可能形成的配子显示在复发中，因此任何后续妊娠都应考虑产前诊断。
A C B Normal Balanced Unbalanced 21 14 Normal and balanced complements.A C B 正常 平衡 不平衡 21 14 正常和平衡的互补体。
(B) Unbalanced, with one product containing both the translocation chromosome and the normal chromosome 21, and the reciprocal product containing chromosome 14.(B) 不平衡型，一个产物同时含有易位染色体和正常21号染色体，另一个产物含有14号染色体。
(C) Unbalanced, one product with both the translocation chromosome and chromosome 14, and the reciprocal product with chromosome 21 only.(C) 不平衡型，一个产物同时含有易位染色体和14号染色体，另一个产物仅含有21号染色体。
Theoretically, there are six possible types of gametes, but three of them appear unable to lead to viable offspring.理论上，有六种可能的配子类型，但其中三种似乎无法产生可存活后代。
Only the three shaded gametes (left) can lead to viable offspring.只有三个阴影配子（左侧）能产生可存活后代。
Theoretically, the three types of gametes will be produced in equal numbers, and thus, the theoretical risk for a child with Down syndrome should be 1 in 3.理论上，这三种类型的配子将等量产生，因此，生育唐氏综合征患儿的理论风险应为三分之一。
However, extensive population studies have shown that unbalanced chromosome complements appear in only ~10% to 15% of the progeny of carrier mothers and in only a few percent of the progeny of carrier fathers who have translocations involving chromosome 21.然而，广泛的人群研究表明，不平衡的染色体互补仅出现在携带者母亲后代的大约10%至15%中，以及涉及21号染色体易位的携带者父亲后代的仅百分之几中。
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 83 Partial Trisomy 21.
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 83 Partial Trisomy 21.疾病的染色体和基因组基础 83 部分三体21.
Very rarely, Down syndrome is diagnosed in a patient in whom only a part of the long arm of chromosome 21 is present in triplicate.极少数情况下，唐氏综合征被诊断于仅染色体21长臂的一部分以三倍体形式存在的患者中。
These patients are of particular significance because they can show what region of chromosome 21 is likely to be responsible for specific components of the Down syndrome phenotype and what regions can be triplicated without causing that aspect of the phenotype.这些患者具有特殊意义，因为他们能显示染色体21的哪个区域可能与唐氏综合征表型的特定组成部分有关，以及哪些区域可以三倍体化而不引起该表型特征。
The most notable success has been the identification of a less than 2-Mb region that is critical for the heart defects seen in ~40% of Down syndrome patients.最显著的成就是识别出一个小于2 Mb的区域，该区域对于约40%唐氏综合征患者中出现的心脏缺陷至关重要。
Sorting out the specific genes crucial to the expression of the Down syndrome phenotype from those that merely happen to be syntenic with them on chromosome 21 is critical for determining the pathogenesis of the various clinical findings.区分那些对唐氏综合征表型表达至关重要的特定基因与那些在染色体21上恰好与之同线的基因，对于确定各种临床表现的发病机制至关重要。
UNIPARENTAL DISOMY Chromosome nondisjunction most commonly results in trisomy or monosomy for the particular chromosome involved in the segregation error.单亲二体 染色体不分离最常见的结果是涉及分离错误的特定染色体出现三体或单体。
However, less commonly, it can also lead to a disomic state in which both copies of a chromosome derive from the same parent, rather than one copy being inherited from the mother and the other from the father.然而，较不常见的是，它也可导致二体状态，其中染色体的两个拷贝均来自同一亲本，而不是一个拷贝来自母亲，另一个来自父亲。
This situation, called uniparental disomy, is defined as the presence of a disomic cell line containing two chromosomes, or portions thereof, that are inherited from only one parent (see If the two chromosomes are derived from identical sister chromatids, the situation is described as isodisomy; if both homologs from one parent are present, the situation is heterodisomy .这种情况称为单亲二体，定义为存在一个二体细胞系，其含有两条染色体或其部分，且仅遗传自一个亲本（若两条染色体来自相同的姐妹染色单体，则称为等二体；若来自一个亲本的两个同源染色体均存在，则称为异二体）。
The most common explanation for uniparental disomy is trisomy rescue due to chromosome nondisjunction in cells of a trisomic conceptus to restore a disomic state.单亲二体最常见的解释是三体胚胎细胞中因染色体不分离而发生的三体拯救，以恢复二体状态。
The cause of the originating trisomy is typical meiotic nondisjunction in one of the parental germlines; the rescue results from a second nondisjunction event, this one occurring mitotically at an early postzygotic stage, thus rescuing a fetus that otherwise would most likely be aborted spontaneously (the most common fate for any trisomic fetus; see Depending on the stage and parent of the original nondisjunction event (i. e., maternal or paternal meiosis I or II), the location of meiotic recombination events, and which chromosome is subsequently lost in the postzygotic mitotic nondisjunction event, the resulting fetus or liveborn can have complete or partial isodisomy or heterodisomy for the relevant chromosome.原始三体的原因是一个亲本生殖细胞系中典型的减数分裂不分离；拯救源于第二次不分离事件，这一次发生在受精后早期的有丝分裂阶段，从而拯救了一个否则很可能自然流产的胎儿（任何三体胎儿最常见的命运；见根据原始不分离事件发生的阶段和亲本（即母源或父源减数分裂I或II）、减数分裂重组的位置以及随后在受精后有丝分裂不分离事件中丢失的染色体，最终胎儿或活产儿可能具有相关染色体的完全或部分等二体或异二体）。
Although it is not known how common uniparental disomy is overall, it has been documented for most chromosomes in the karyotype by demonstrating uniparental inheritance of polymorphisms in a family.尽管尚不清楚单亲二体总体上有多常见，但已通过在一个家系中证明多态性的单亲遗传，在核型中大多数染色体上均有记录。
Clinical abnormalities, however, have been demonstrated for only some of these, typically in cases when an imprinted region is present in two copies from one parent (see the section on genomic imprinting later in this chapter) or when a typically recessive condition (which would ordinarily imply that both parents are obligate carriers; see Chapter 7) is observed in a patient who has only one documented carrier parent.然而，仅在其中一些染色体上证明了临床异常，通常是在以下情况：一个印迹区域以两个拷贝来自同一亲本（见本章后文关于基因组印迹的章节），或者当一个典型隐性遗传病（通常意味着父母双方均为强制携带者；见第7章）出现在仅有一个已知携带者亲本的患者中时。
It is important to stress that, although such conditions frequently come to clinical attention because of variants in individual genes or in imprinted regions, the underlying mechanism in cases of uniparental disomy is abnormal chromosome segregation.必须强调的是，尽管此类情况常因单个基因或印迹区域变异而引起临床关注，但单亲二体病例的根本机制是染色体分离异常。
Other Disorders Due to Uniparental Disomy Although it is unclear how common uniparental disomy is, it may provide an explanation for a disease when an imprinted region (see the section on genomic imprinting later in this chapter) is present in two copies from one parent.其他因单亲二体导致的疾病 尽管尚不清楚单亲二体有多常见，但当印迹区域（见本章后文关于基因组印迹的章节）以两个拷贝来自同一亲本时，它可能为某种疾病提供解释。
Thus physicians and genetic counselors must keep imprinting in mind as a possible cause of genetic disorders.因此，医生和遗传咨询师必须牢记印迹是遗传疾病的一个可能原因。
For example, a few patients with cystic fibrosis and short stature have been described with two identical copies of most or the entirety of their maternal chromosome 7.例如，已报道少数囊性纤维化和身材矮小的患者具有大部分或全部母源染色体7的两个相同拷贝。
In these cases, the mother happened to be a carrier for cystic fibrosis (Case 12), and because the child received two maternal copies of the mutant cystic fibrosis gene and no paternal copy of the normal allele at this locus, the child developed the disease.在这些病例中，母亲恰好是囊性纤维化的携带者（病例12），并且因为孩子接受了两个母源突变囊性纤维化基因拷贝，而没有此位点的父源正常等位基因拷贝，孩子发病。
The growth failure was unexplained but might be related to loss of unidentified paternally imprinted genes on chromosome 7.生长障碍原因不明，但可能与染色体7上未识别的父源印迹基因缺失有关。
STRUCTURAL VARIANTS AND CLINICAL IMPACT Structural variants (SVs) are typically defined as changes in DNA that are 50 bp or greater in size.结构变异与临床影响 结构变异通常定义为大小在50 bp或以上的DNA改变。
SVs have different types, such as deletions, duplications, insertions, inversions, and translocations, and can potentially impact molecular and cellular processes, regulatory functions, 3D structure, and transcriptional machinery (see Chapter 4).结构变异有不同的类型，如缺失、重复、插入、倒位和易位，并且可能影响分子和细胞过程、调控功能、三维结构和转录机制（见第4章）。
SVs also include insertions and deletions of mobile elements.结构变异还包括移动元件的插入和缺失。
Some examples of mobile elements include long interspersed element 1 (LINE-1), Alu, short interspersed element (SINE), variable-number tandem repeat (VNTR), and SINE-R/VNTR/Alu (SVA) (see Chapter 2).移动元件的一些例子包括长散布元件1（LINE-1）、Alu、短散布元件（SINE）、可变数目串联重复（VNTR）和SINE-R/VNTR/Alu（SVA）（见第2章）。
Mobile element insertions into the DNA of gametes or the early embryo can disrupt genes or regulatory elements leading to disease ( The Impact of Genetic Diversity The 1000 Genomes Project (1000GP) was initiated to identify genetic variation in the human genome across diverse populations, and it has been instrumental in generating the largest catalog of genomic variants.移动元件插入到配子或早期胚胎DNA中可破坏基因或调控元件，导致疾病（遗传多样性的影响：千人基因组计划（1000GP）旨在识别不同人群中人类基因组的遗传变异，并且在生成最大的基因组变异目录方面发挥了重要作用。
The 1000GP structural variation analysis group, known as Human Genome Structural Variation Consortium (HGSVC), aims to identify a high-quality map of SVs千人基因组计划结构变异分析小组，即人类基因组结构变异联盟，旨在识别一个高质量的结构变异图谱。
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and develop new methods to take advantage of both traditional and new genome analysis techniques.
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and develop new methods to take advantage of both traditional and new genome analysis techniques.并开发新方法以充分利用传统和新的基因组分析技术。
Two recent publications from HGSVC not only identify novel variants, including single-nucleotide variants (SNVs), insertions, and deletions, and SVs but also indicated the importance of adopting new technologies, such as longread sequencing, Strand-Seq, and optical mapping to reveal previously uncharacterized regions of the genome and detect novel variants.HGSVC近期发表的两篇论文不仅鉴定了新变异，包括单核苷酸变异（SNV）、插入缺失和结构变异（SV），还指出采用长读长测序、链测序和光学图谱等新技术的重要性，以揭示此前未表征的基因组区域并检测新变异。
The vast majority of genomic Blue color represents paternal and maroon color represents chromosomes of maternal origin.蓝色代表父源染色体，栗色代表母源染色体。
The nondisjunction could arise in either the maternal or paternal germline.不分离可能发生在母系或父系生殖系中。
(B) Heterodisomy and isodisomy examples represented.(B) 异二体性与同二体性的示例所示。
Three offsprings with the following chromosomes are observed: normal biparental inheritance of the example chromosome, maternal heterodisomy with one of each of the mother’s chromosomes, and two potential types of uniparental isodisomy with two copies of either of the mother’s chromosomes (denoted as a and b). )观察到三个子代具有以下染色体：示例染色体的正常双亲遗传、母源异二体性（含母亲每条染色体各一份），以及两种潜在类型的母源单亲同二体性（含母亲任一染色体的两份拷贝，分别标记为a和b）。
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 85 variant data derive from individuals of European des­ cent residing in W…
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 85 variant data derive from individuals of European des­ cent residing in Western countries, which might cause incorrect clinical interpretation of genomic variants.疾病的染色体和基因组基础 85 变异数据来源于居住在西方国家的欧洲裔个体，这可能导致基因组变异的临床解读不正确。
Strikingly, a recent study showed that the African pangenome, built using sequence data from 910 individuals of African descent, contained ~10% more DNA not present in the human reference genome assembly, GRCh 38, suggesting that the current reference genome may not fully represent genomic variation in diverse human populations.引人注目的是，一项近期研究表明，利用910名非洲裔个体的序列数据构建的非洲泛基因组，包含了约10%额外的人类参考基因组组装GRCh38中不存在的DNA，提示当前参考基因组可能未完全代表不同人群的基因组变异。
This is further evidence of the need for de novo assemblies of a large number of genomes from underrepresented populations, in order to comprehensively assess the variation in the human genome.这进一步证明了需要从代表性不足的人群中对大量基因组进行从头组装，以全面评估人类基因组中的变异。
A study by Kessler and colleagues suggested that the lack of individuals of African ancestry in variant databases may have resulted in the mischaracterization of variants in the Clin Var and the Human Gene Mutation Databases highlighting the fact that additional studies are required to get a better understanding of the human genome diversity and its clinical impact.Kessler及其同事的一项研究提示，变异数据库中缺乏非洲裔个体可能导致ClinVar和人类基因突变数据库中变异被错误分类，突显出需要更多研究以更好地理解人类基因组多样性及其临床影响。
Several recent large-scale sequencing studies in underrepresented populations, including people of African, Asian, Latinx, and Native American ancestry, have been uploaded to publicly available resources, such as the Genome Aggregation Database (gnom AD).近期几项针对代表性不足人群（包括非洲裔、亚洲裔、拉丁裔和美洲原住民）的大规模测序研究已上传至公共资源库，例如基因组聚合数据库（gnomAD）。
Segmental Duplications, Copy Number Variants, and Nonallelic Homologous Recombination Approximately 5% of the human genome consists of low copy repeats called segmental duplications (SDs) that are 1000 bp or greater in size, with paralogous copies (duplicated copies descended from the same ­origin) ­sharing 90% or more sequence identity.节段性重复、拷贝数变异和非等位基因同源重组 人类基因组中约5%由称为节段性重复（SD）的低拷贝重复组成，其大小≥1000 bp，旁系同源拷贝（源自同一祖先的重复拷贝）共享≥90%的序列一致性。
Paralogous copies of SDs either can be in tandem, exist on the same chromosome at some distance (i. e., intrachromosomal SDs), or they can be found on different chromosomes (i. e., interchromosomal SDs).SD的旁系同源拷贝可以串联排列，存在于同一染色体上一定距离处（即染色体内SD），或者位于不同染色体上（即染色体间SD）。
Different SDs can be clustered together into complex regions called SD blocks .不同的SD可以聚集成称为SD块的复杂区域。
High sequence identity between paralogous copies of SDs makes them an excellent substrate for nonallelic homologous recombination (NAHR) .SD旁系同源拷贝之间的高序列一致性使其成为非等位基因同源重组（NAHR）的优良底物。
NAHR refers to aberrant recombination resulting from the misalignment of two highly similar paralogous copies of SDs, which further leads to SVs, including deletions, duplications, translocations, and inversions.NAHR是指由于两个高度相似的SD旁系同源拷贝错配而导致的异常重组，进而引发结构变异（SV），包括缺失、重复、易位和倒位。
NAHR is a mechanism that has been shown to cause several genomic disorders, such as Williams-Beuren syndrome (WBS) on chromosome 7q11. 23, 15q13. 3 microdeletion/microduplication syndrome, 16p11. 2 microdeletion/microduplication syndrome, and 22q11. 2 deletion syndrome (DS) and cateye syndrome (CES) (22q11. 2 duplication syndrome) on chromosome 22q11. 2.NAHR是一种已被证实可导致多种基因组疾病的机制，例如7q11.23染色体区域的威廉姆斯-博伊伦综合征（WBS）、15q13.3微缺失/微重复综合征、16p11.2微缺失/微重复综合征，以及22q11.2染色体区域的22q11.2缺失综合征（DS）和猫眼综合征（CES）（即22q11.2重复综合征）。
The Impact of Inversions in Genomic Disorders It is estimated that there are more than 3400 inversions described among humans (based on Database of Genomic Variants 2020-02-05 GRCh 38 variant list).倒位在基因组疾病中的影响 据估计，人类中已描述超过3400种倒位（基于基因组变异数据库2020-02-05 GRCh38变异列表）。
An average human genome carries as many as 156 inversions.平均每个人类基因组携带多达156个倒位。
Inversions can predispose a person to the formation of a new SV that may lead to a genomic disorder.倒位可使人易于形成新的结构变异，进而可能导致基因组疾病。
For instance, a study has shown that a ~1. 2-Mb inversion in the 7q11. 23 region is found in 25% of the parent of origin chromosomes of probands with WBS.例如，一项研究表明，在WBS先证者中，25%的亲本来源染色体上发现了7q11.23区域约1.2 Mb的倒位。
In other cases, inversions do not seem to have an increased propensity to form a new SV that causes a genomic disorder.在其他情况下，倒位似乎并未增加形成导致基因组疾病的新结构变异的倾向。
For example, a recent study showed that among the 2 region of the human genome are represented.例如，一项近期研究表明，人类基因组的2区域被代表。
Black rectangles, SDA and SDB, represent two SD blocks.黑色矩形SDA和SDB代表两个SD块。
Yellow, black, and gray colored rectangles within SD blocks represent individual SDs, and signs embedded to each SD show orientation (&gt;: direct, &lt;: inverted).SD块内的黄色、黑色和灰色矩形代表单个SD，每个SD内嵌入的符号表示方向（>: 正向，<: 反向）。
Text next to each SD shows the genomic position of the other highly similar copy, known as paralogous copy.每个SD旁边的文本显示另一个高度相似拷贝（称为旁系同源拷贝）的基因组位置。
SDs can be intrachromosomal (A, red rectangles), paralogous copy is present on the same chromosome (chr 7), or interchromosomal (B, blue rectangles), paralogous copy is present on a different chromosome (chr 10).SD可以是染色体内的（A，红色矩形），旁系同源拷贝存在于同一染色体（chr 7）上；或是染色体间的（B，蓝色矩形），旁系同源拷贝存在于不同染色体（chr 10）上。
(Image is obtained from University of California Santa Cruz Genome Browser.)（图片来源于加利福尼亚大学圣克鲁兹分校基因组浏览器。）
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22 parents of probands with the 3q29 deletion syndrome, six carried the ~289-kb inversion within SDA and SDB, and three …
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22 parents of probands with the 3q29 deletion syndrome, six carried the ~289-kb inversion within SDA and SDB, and three of the affected probands inherited the inversion on the intact chromosome.在3q29缺失综合征先证者的22位父母中，有6位携带SDA和SDB内约289kb的倒位，且其中3位受累先证者从完整染色体上遗传了该倒位。
However, none of the parent of origin chromosomes carried the larger inversion (~2 Mb) within SDA and SDC, which might caused a pathogenic deletion in probands.然而，亲源染色体均未携带SDA和SDC内较大的倒位（约2 Mb），该倒位可能导致了先证者中的致病性缺失。
Deletion and Duplication Syndromes Genomic disorders result from gain or loss of hundreds of kilobases of DNA.缺失和重复综合征 基因组疾病由数百千碱基DNA的增加或缺失引起。
There are at least two mechanisms whereby SVs can be formed that lead to genomic disorders.至少有两种机制可导致结构变异形成，从而引发基因组疾病。
NAHR leads to recurrent SVs, whereas nonhomologous end joining (NHEJ) and other nonhomologous recombination repair mechanisms lead to nonrecurrent SVs.非等位基因同源重组导致复发性结构变异，而非同源末端连接及其他非同源重组修复机制则导致非复发性结构变异。
Recurrent Structural variants NAHR is the key mechanism causing recurrent SVs.复发性结构变异 非等位基因同源重组是导致复发性结构变异的关键机制。
These rearrangements usually have the same size in unrelated individuals because the breakpoints are localized to interspersed, highly similar paralogous copies of SDs.这些重排在不相关个体中通常具有相同大小，因为断点定位于分散的、高度相似的节段性重复旁系同源拷贝上。
Extensive analysis of over 30,000 patients worldwide has now implicated this general sequence-dependent mechanism in 50 to 100 syndromes involving contiguous gene rearrangements, which collectively are sometimes referred to as genomic disorders.对全球超过30,000名患者的广泛分析现已表明，这种普遍的序列依赖性机制涉及50至100种包含连续基因重排的综合征，这些综合征有时统称为基因组疾病。
Here we focus A C B Nonallelic homologous recombination (NAHR), unequal crossing over between misaligned sister chromatids or homologous chromosomes containing highly homologous copies of segmental duplications can lead to deletion or duplication.此处我们聚焦于A C B 非等位基因同源重组（NAHR）：错配的姐妹染色单体或含有节段性重复高度同源拷贝的同源染色体之间的不等交换可导致缺失或重复。
(B) Nonhomologous end joining (NHEJ), double-strand breaks (DSBs) occur and NHEJ polymerase, nuclease, and ligase complexes initiate SV formation.(B) 非同源末端连接（NHEJ）：发生双链断裂，NHEJ聚合酶、核酸酶和连接酶复合物启动结构变异形成。
Red dashed boxes represent microhomology between the two DNA ends, which is used to guide end joining.红色虚线框代表两个DNA末端之间的微同源区，用于引导末端连接。
The process could result in structural variant formation.该过程可导致结构变异形成。
(C) Fork stalling or template switching (Fo STe S) and microhomology-mediated break-induced replication (MMBIR) model is represented.(C) 展示了复制叉停滞或模板切换（FoSTeS）以及微同源介导的断裂诱导复制（MMBIR）模型。
When a replication fork encounters a nick (striking arrowhead) in a template strand, one arm of the fork breaks off and results in a collapsed fork.当复制叉遇到模板链上的切口（箭头标示）时，复制叉的一臂断裂，导致复制叉塌陷。
At the single double-strand end, the 5′ end of the lagging strand (dashed black lines) is resected, giving a 30 overhang.在单个双链末端，后随链（黑色虚线）的5′端被切除，产生一个3′突出端。
The 3′ single-strand end of lagging-strand template (solid red lines) invades the sister leading-strand DNA (gray lines) guided by regions of microhomology (MH), forming a new replication fork.后随链模板（红色实线）的3′单链末端在微同源区（MH）引导下侵入姐妹前导链DNA（灰色线），形成新的复制叉。
The 3′ end invasion of the lagging-strand template can reform replication forks on different genomic templates before returning to the original sister chromatid and forming a processive replication fork that completes replication.后随链模板的3′端侵入可在不同基因组模板上重新形成复制叉，之后返回原始姐妹染色单体并形成持续复制叉以完成复制。
Each line represents a DNA nucleotide strand.每条线代表一条DNA核苷酸链。
New DNA synthesis is shown by dashed lines.新DNA合成由虚线表示。
For examples of genomic disorders, segmental duplications, and the size of the deleted or duplicated region, see )基因组疾病、节段性重复以及缺失或重复区域大小的示例，请参见 )
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 87 on syndromes involving chromosome 22 to illustrate underlying genomic fe…
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 87 on syndromes involving chromosome 22 to illustrate underlying genomic features of this class of disorders.疾病的染色体与基因组基础 87：涉及22号染色体的综合征，以阐明该类疾病的潜在基因组特征。
Deletions and Duplications Involving Chromosome 22q11. 2.涉及染色体22q11.2的缺失和重复。
A particularly common deletion, 1 in 3400 live births, involves deletions at chromosome region 22q11. 2 and is referred to as 22q11. 2 deletion syndrome (DS), or Di George syndrome, or velocardiofacial syndrome.一种特别常见的缺失，在3400例活产中有1例，涉及染色体区域22q11.2的缺失，被称为22q11.2缺失综合征(DS)，或Di George综合征，或腭心面综合征。
This clinical syndrome is caused by a deletion of ~3 Mb within 22q11. 2 on one copy of chromosome 22.该临床综合征是由一条22号染色体上22q11.2内约3 Mb的缺失引起的。
The deletion and other rearrangements of this region shown in 22q11. 2 distal deletions 2 3 1 No. copies of 22q11. 2 4 3 Mb or C A B 2 mediated by homologous recombination between segmental duplications.该区域的缺失和其他重排，如22q11.2远端缺失所示（2、3、1、22q11.2拷贝数、4、3 Mb或C、A、B、2），由节段重复之间的同源重组介导。
(A) Normal karyotypes show two copies of 22q11. 2, each containing multiple copies of a family of related segmental duplications within the region (dark blue).(A) 正常核型显示两条22q11.2拷贝，每条在该区域内包含多个相关节段重复家族的拷贝（深蓝色）。
In Di George syndrome (DGS) or velocardiofacial syndrome (VCFS), a 3-Mb region is deleted from one homologue, removing ~30 genes; in ~10% of patients, a smaller 1. 5-Mb deletion (nested within the larger segment) is deleted.在Di George综合征(DGS)或腭心面综合征(VCFS)中，一条同源染色体上缺失了一个3 Mb的区域，移除约30个基因；约10%的患者存在一个较小的1.5 Mb缺失（嵌套在较大片段内）。
The reciprocal duplication is seen in patients with dup(22)(q 11. 2q11. 2).在dup(22)(q11.2q11.2)患者中可见相互重复。
Tetrasomy for 22q11. 2 is seen in patients with cat-eye syndrome.在猫眼综合征患者中可见22q11.2四体性。
Note that the duplicated region in the cat-eye syndrome chromosome is in an inverted orientation relative to the duplication seen in dup(22) patients, indicating a more complex genomic rearrangement involving these segmental duplications.注意，猫眼综合征染色体中的重复区域与dup(22)患者中见到的重复方向相反，表明涉及这些节段重复的更复杂的基因组重排。
(B) Expanded view of the 22q11. 2 genomic region, indicating the common DGS/VCFS deletions (red) and more distal deletions (also mediated by recombination involving segmental duplications) that are seen in patients with other phenotypes (orange).(B) 22q11.2基因组区域的放大视图，显示常见的DGS/VCFS缺失（红色）和更远端的缺失（也由涉及节段重复的重组介导），这些缺失见于其他表型的患者（橙色）。
Genes in the region (from www. genome. ucsc. edu browser) are indicated above the region.该区域内的基因（来自www.genome.ucsc.edu浏览器）标示在区域上方。
(C) Two-color fluorescence in situ hybridization analysis of proband with DGS, demonstrating deletion of 22q11. 2 on one homologue.(C) 对DGS先证者进行双色荧光原位杂交分析，显示一条同源染色体上22q11.2的缺失。
Green signal is hybridization to a control region in distal 22q.绿色信号杂交至远端22q的对照区域。
Red signal shows hybridization to a region in proximal 22q that is present on one copy of the chromosome but deleted from the other (arrow).红色信号显示杂交至近端22q的一个区域，该区域存在于一条染色体拷贝上，但在另一条上缺失（箭头）。
(C, fluorescence in situ hybridization image courtesy Kato T, Kosaka K, Kimura M, et al: Thrombocytopenia in patients with 22q11. 2 deletion syndrome and its association with glycoprotein Ib-β, Genet Med 5:113–119, 2003.)(C, 荧光原位杂交图像由Kato T、Kosaka K、Kimura M等人提供：22q11.2缺失综合征患者的血小板减少症及其与糖蛋白Ib-β的关联，Genet Med 5:113–119, 2003.)
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The general concepts illustrated for disorders associated with 22q11. 2 also apply to many other chromosomal and genomic…
Ch6 — Segment 10
The general concepts illustrated for disorders associated with 22q11. 2 also apply to many other chromosomal and genomic disorders, some of the most common or more significant of which are summarized in 1.[TL:failed]
Nonrecurrent Structural Variants Nonrecurrent SVs usually do not have the same size in unrelated individuals.[TL:failed]
The breakpoints of these rearrangements can be localized to anywhere in the genome and are often characterized by microhomologies, small insertions, or blunt ends.[TL:failed]
At least 70 genomic disorders have now been shown to be caused by nonrecurrent SVs.[TL:failed]
Although NHEJ is the presumed mechanism for many of these rearrangements, other mechanisms for nonrecurrent SV formation include DNA replication during the aberrant repair and include fork stalling or template switching (Fo STe S) and microhomologymediated break-induced replication (MMBIR) .[TL:failed]
In each of these mechanisms, a stalled replication fork is repaired using microhomology to prime for DNA synthesis.[TL:failed]
Nonrecurrent Chromosome Abnormalities Whereas the abnormalities just described are mediated by the landscape of specific genomic features in particular chromosomal regions, many other chromosome abnormalities are due to deletions or rearrangements that have no definitive mechanistic basis (see There are 1 deletion/ duplication syndrome 1q21. 1 Deletion/ duplication ≈0. 8 3q29 deletion/ duplication syndrome 3q29 Deletion/ duplication ~1. 6 Williams syndrome 7q11. 23 Deletion ≈1. 6 Prader-Willi/Angelman syndrome 15q11-q 13 Deletion ≈3. 5 16p11. 2 deletion/ duplication syndrome 16p11. 2 Deletion/ duplication ≈0. 6 Smith-Magenis syndrome 17p11. 2 Deletion ≈3. 7 dup(17)(p 11. 2p11. 2) Duplication Di George syndrome/ velocardiofacial syndrome 22q11. 2 Deletion ≈3. 0, 1. 5 Cat-eye syndrome/22q11. 2 duplication syndrome Duplication Azoospermia (AZFc) Yq 11. 2 Deletion ≈3. 5 1 LESSONS FROM GENOMIC DISORDERS Genomic disorders collectively illustrate a number of concepts of general importance for considering the causes and consequences of chromosomal or genomic imbalance.[TL:failed]
First, with few exceptions, altered gene dosage for any extensive chromosomal or genomic region is likely to result in a clinical abnormality, the phenotype of which will, in principle, reflect haploinsufficiency for or overexpression of one or more genes encoded within the region.[TL:failed]
In some cases, the clinical presentation appears to be accounted for by dosage imbalance for just a single gene; in other syndromes, however, the phenotype appears to reflect imbalance for multiple genes across the region.[TL:failed]
Second, the distribution of these duplication/deletion disorders around the genome appears not to be random because the location of families of SDs, especially in pericentromeric and subtelomeric regions, predisposes particular regions to the unequal recombination events that underlie these syndromes.[TL:failed]
Third, even patients carrying what appears to be the same chromosomal deletion or duplication can present with a range of variable phenotypes.[TL:failed]
Although the precise basis for this variability is unknown, it could be due to nongenetic causes, underlying genetic variation in the region on the nondeleted chromosome, or differences elsewhere in the genome among unrelated individuals. many reports of cytogenetically detectable abnormalities in dysmorphic patients involving events such as deletions, duplications, or translocations of one or more chromosomes in the karyotype .[TL:failed]
Overall, cytogenetically visible autosomal deletions occur with an estimated incidence of 1 in 7000 live births.[TL:failed]
Most of these have been seen in only a few patients and are not associated with recognized clinical syndromes.[TL:failed]
Others, however, are sufficiently common to allow delineation of clearly recognizable syndromes in which a series of patients have similar abnormalities.[TL:failed]
The defining mechanistic feature of this class of abnormalities is that the underlying chromosomal event is nonrecurrent (see Autosomal Deletion Syndromes One long-recognized syndrome is the cri du chat ­syndrome, in which there is either a terminal or interstitial deletion of part of the short arm of chromosome 5.[TL:failed]
This deletion syndrome was given its common name because crying infants with this disorder sound like a meowing cat.[TL:failed]
The facial appearance is distinctive and includes microcephaly, hypertelorism, epicanthal folds, low-set ears, sometimes with preauricular tags, and micrognathia.[TL:failed]
The overall incidence of the deletion is estimated to be as high as 1 in 15,000 to 50,000 live births.[TL:failed]
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 89 Most cases of cri du chat syndrome are sporadic; only 10% to 15% of the …
Ch6 — Segment 11
THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 89 Most cases of cri du chat syndrome are sporadic; only 10% to 15% of the patients are the offspring of translocation carriers.疾病的染色体和基因组基础 89 大多数猫叫综合征病例为散发性；仅10%至15%的患者是易位携带者的后代。
The breakpoints and extent of the deleted segment of chromosome 5p are highly variable among different individuals, but the critical region missing in all patients with the phenotype has been identified as band 5p15.5p染色体缺失片段的断点和范围在不同个体间高度可变，但所有具有该表型的患者中缺失的关键区域已被确定为5p15带。
Many of the clinical findings have been attributed to haploinsufficiency for a gene or genes within specific regions; the degree of intellectual impairment usually correlates with the size of the deletion, although genomic studies suggest that haploinsufficiency for particular regions within 5p14-p 15 may contribute disproportionately to severe intellectual disability .许多临床表现归因于特定区域内一个或多个基因的单倍体剂量不足；智力障碍的程度通常与缺失大小相关，尽管基因组研究表明，5p14-p15内特定区域的单倍体剂量不足可能对严重智力障碍有不成比例的贡献。
Although many large deletions can be appreciated by routine karyotyping, detection of other nonrecurrent deletions requires more detailed analysis by microarrays; this is particularly true for abnormalities involving subtelomeric bands of many chromosomes, which can be difficult to visualize well by routine chromosome banding.虽然许多大片段缺失可通过常规核型分析识别，但其他非复发性缺失的检测需要通过微阵列进行更详细的分析；对于涉及许多染色体亚端粒带的异常尤其如此，这些异常通常难以通过常规染色体显带技术清晰显示。
For example, one of the most common nonrecurrent abnormalities, the chromosome 1p36 deletion syndrome, has a population incidence of 1 in 5000 and involves a wide range of different breakpoints, all within the terminal 10 Mb of chromosome 1p.例如，最常见的非复发性异常之一——染色体1p36缺失综合征，人群发病率为1/5000，涉及多种不同断点，均位于染色体1p末端10 Mb区域内。
Approximately 95% of cases are de novo, and many (e. g., the case illustrated in are not detectable by routine chromosome analysis.大约95%的病例为新发，且许多（例如图示的病例）无法通过常规染色体分析检测到。
Typically, and in contrast to the genomic disorders presented in 3 15. 2 15. 1 14 13. 3 13. 1 13. 2 Position on 5p (Mb) 40 30 20 10 Speech Cat cry Facial phenotype Intellectual disability Intellectual disability Intellectual disability 0 p 36. 32 p 36. 23 p 36. 21 p 36. 12 p 35. 2 p 35. 1 p 34. 2 p 33 p 32. 2 p 31. 3 p 31. 1 p 22. 2 p 21. 3 p 21. 1 p 13. 2 p 12 -4 -2 -1 0 +1 +2 +4 D E A B C 4p- deletion syndrome is illustrated by two children supported by 4p-supportgroup. org: (A) Kamila’s smile reveals missing teeth.通常，与前面介绍的基因组疾病相比，3 15.2 15.1 14 13.3 13.1 13.2 5p上的位置（Mb） 40 30 20 10 语言 猫叫 面部表型 智力障碍 智力障碍 智力障碍 0 p36.32 p36.23 p36.21 p36.12 p35.2 p35.1 p34.2 p33 p32.2 p31.3 p31.1 p22.2 p21.3 p21.1 p13.2 p12 -4 -2 -1 0 +1 +2 +4 D E A B C 4p-缺失综合征通过两个由4p-supportgroup.org支持的儿童示例说明：(A) Kamila的微笑显示缺牙。
(B) Sadie shows what some describe as a Greek warrior helmet facial phenotype.(B) Sadie展示了有些人描述为希腊战士头盔的面部表型。
(C) Brielle lives with Cri du chat syndrome (fivepminus. org); here, illustrating characteristic hypertelorism, short philtrum, and epicanthal folds.(C) Brielle患有猫叫综合征（fivepminus.org）；图中展示了其特征性的眼距过宽、人中短以及内眦赘皮。
(D) Phenotype-karyotype map of chromosome 5p, based on chromosomal microarray analysis of a series of del(5p) patients.(D) 基于一系列del(5p)患者的染色体微阵列分析绘制的5p染色体表型-核型图谱。
(E) Chromosomal microarray analysis of ~5-Mb deletion in band 1p36. 3 (red), which is undetectable by conventional karyotyping.(E) 1p36.3带中约5 Mb缺失的染色体微阵列分析（红色），该缺失无法通过常规核型分析检测到。
(A, B and C, Photographs by Rick Guidotti, Positive Exposure, www. positiveexposure. org; D, based on data from Zhang X, Snijders A, Segraves R, et al: High-resolution mapping of genotype-phenotype relationships in cri du chat syndrome using array comparative genome hybridization, Am J Hum Genet 76:312–326, 2005; E, courtesy M.(A、B和C照片由Rick Guidotti拍摄，Positive Exposure提供，www.positiveexposure.org；D基于Zhang X, Snijders A, Segraves R等人数据：使用阵列比较基因组杂交技术高分辨率定位猫叫综合征基因型-表型关系，Am J Hum Genet 76:312–326, 2005；E承蒙M.提供。
Katharine Rudd, Emory Genetics Laboratory, Atlanta, Georgia.)Katharine Rudd，埃默里遗传学实验室，亚特兰大，佐治亚州。）
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in 6q deletion , interstitial deletion of a subtelomeric segment, or recombination between copies of repetitive elements…
Ch6 — Segment 12
in 6q deletion , interstitial deletion of a subtelomeric segment, or recombination between copies of repetitive elements, such as Alu or LINE-1 (see Chapter 2).在6q缺失中，涉及亚端粒区段的间质缺失，或重复元件（如Alu或LINE-1，见第2章）拷贝之间的重组。
Balanced Translocations With Developmental Phenotypes Reciprocal translocations are relatively common (see Chapter 5).具有发育表型的平衡易位：相互易位相对常见（见第5章）。
Most are balanced and involve the precise exchange of chromosomal material between nonhomologous chromosomes; as such, they usually do not have an obvious phenotypic effect.大多数为平衡易位，涉及非同源染色体之间染色体物质的精确交换；因此，它们通常不产生明显的表型效应。
However, among the ~1 in 2000 newborns who have a de novo balanced translocation, the risk for a congenital abnormality is empirically elevated several-fold, leading to the suggestion that some balanced translocations involve direct disruption of a gene or genes by one or both of the translocation breakpoints.然而，在约1/2000的新生儿中，存在新发平衡易位，其先天性异常的风险经验性地升高数倍，提示某些平衡易位涉及一个或多个基因被易位断点直接破坏。
Detailed analysis of a number of such cases by fluorescence in situ hybridization (FISH), microarrays, and targeted or whole genome sequencing has identified defects in protein-coding or noncoding RNA genes in patients with various phenotypes, ranging from developmental delay to congenital heart defects to autism spectrum disorders.通过荧光原位杂交、微阵列以及靶向或全基因组测序对大量此类病例的详细分析，已识别出具有不同表型（从发育迟缓到先天性心脏缺陷，再到自闭症谱系障碍）的患者中蛋白质编码或非编码RNA基因的缺陷。
Although the clinical abnormalities in these cases can be ascribed to variants in individual genes located at the site of the translocations, the underlying mechanism in each case is the chromosomal rearrangement itself (see Segregation of Familial Abnormalities The mechanism of pathogenesis here is distinguished from the mechanism of nondisjunction described earlier in this chapter.尽管这些病例中的临床异常可归因于易位位点上的单个基因变异，但每种病例的根本机制是染色体结构重排本身（见家族性异常的分离：这里的发病机制与本章前面描述的不分离机制相区别）。
In contrast to aneuploidy or uniparental disomy, it is not the process of segregation that is abnormal in these cases; rather, it is the random nature of events during segregation that leads to unbalanced karyotypes and thus to offspring with abnormal phenotypes.与非整倍体或单亲二体相比，这些病例中异常的并非分离过程；相反，是分离过程中事件的随机性导致了不平衡核型，从而产生具有异常表型的后代。
In the case of balanced translocations, for example, because the chromosomes involved form a quadrivalent in meiosis, the particular combination of chromosomes transmitted to a given gamete can lead to genomic imbalance , even though the segregation is itself normal.例如，在平衡易位的情况下，由于涉及的染色体在减数分裂中形成四价体，传递给特定配子的染色体特定组合可导致基因组不平衡，尽管分离本身正常。
Another type of familial structural abnormality that illustrates this mechanism involves inversion chromosomes.另一类阐明此机制的家族性结构异常涉及倒位染色体。
In this case, segregation of the inverted chromosome and its normal homologue during meiosis is typically uneventful; however, unbalanced gametes can be produced as a result of the process of recombination occurring within the inverted segment, in particular for pericentric inversions .在这种情况下，减数分裂期间倒位染色体与其正常同源染色体的分离通常无异常；然而，由于倒位区段内发生的重组过程（特别是着丝粒周围倒位）可产生不平衡配子。
Different inversion chromosomes carry different risks for abnormal offspring, presumably reflecting both the likelihood that a recombination event will occur within the inverted segment and the likelihood that an unbalanced gamete can lead to viable offspring.不同的倒位染色体对异常后代的风险不同，这既反映了倒位区段内发生重组事件的可能性，也反映了不平衡配子产生可存活后代的可能性。
This overall risk must be determined empirically for use in genetic counseling.这种总体风险必须通过经验确定，以用于遗传咨询。
Several well-described inversions illustrate this point.数个描述详尽的倒位实例阐明了这一点。
A pericentric inversion of chromosome 3 is one of the few for which sufficient data have been obtained to allow an estimate of the transmission of the inversion chromosome to the offspring of carriers.3号染色体的着丝粒周围倒位是少数几个已获得足够数据以估计倒位染色体传递给携带者后代概率的倒位之一。
The inv(3) (p 25q21) originated in a couple from Newfoundland in the early 1800s and has since been reported in a number of families whose ancestors can be traced to the Atlantic provinces of Canada.inv(3)(p25q21)起源于19世纪初纽芬兰的一对夫妇，随后在多个祖先可追溯至加拿大大西洋省份的家系中被报道。
Carriers of the inv(3) chromosome are normal, but some of their offspring have a characteristic abnormal phenotype associated with the presence of a recombinant chromosome 3, in which there is duplication of the segment distal to 3q21 and deficiency of the segment distal to 3p25.inv(3)染色体的携带者表现正常，但其部分后代具有特征性的异常表型，与存在重组3号染色体相关，该染色体表现为3q21远端区段重复和3p25远端区段缺失。
The other predicted unbalanced gamete, with duplication of distal 3p and deficiency of distal 3q, does not lead to viable offspring.另一种预测的不平衡配子（具有远端3p重复和远端3q缺失）不能产生可存活后代。
The empirical risk for an abnormal pregnancy outcome in inv(3) carriers is greater than 40% and indicates the importance of family chromosome studies to identify carriers and to offer genetic counseling and prenatal diagnosis.inv(3)携带者异常妊娠结局的经验风险大于40%，表明进行家族染色体研究以识别携带者并提供遗传咨询和产前诊断的重要性。
Not all pericentric inversions have a risk for abnormal offspring, however.然而，并非所有着丝粒周围倒位都会带来异常后代的风险。
One of the most common inversions Green and red signals reveal intact subtelomeric sequences on the short and long arms of chromosome 6.最常见的倒位之一：绿色和红色信号显示6号染色体短臂和长臂上的完整亚端粒序列。
In this metaphase spread from a patient with congenital abnormalities, we can see the loss of the red signal from one of the chromosome 6 s, consistent with a deletion of materials near the long arm terminus of that chromosome.在此例先天性异常患者的中期分裂象中，我们观察到其中一条6号染色体上的红色信号缺失，与该染色体长臂末端附近物质缺失一致。
(Courtesy , The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, United States.)（图片由美国康涅狄格州法明顿的杰克逊基因组医学实验室提供。）
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 91 seen in human chromosomes is a small pericentric inversion of chromosome…
Ch6 — Segment 13
THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 91 seen in human chromosomes is a small pericentric inversion of chromosome 9, which is present in up to 1% of all individuals.疾病的染色体与基因组基础 人类染色体中常见的一种变异是9号染色体的小着丝粒周围倒位，见于高达1%的个体。
The inv(9)(p 11q12) has no known deleterious effect on carriers and does not appear to be associated with a significant risk for miscarriage or unbalanced offspring; the empirical risk is not different from that of the population at large, and it is therefore generally considered a normal variant.inv(9)(p11q12)对携带者无已知有害效应，且似乎与流产或不平衡后代的显著风险无关；经验风险与一般人群无差异，因此通常被视为正常变异。
Neurodevelopmental Disorders and Intellectual Disability Next we consider another class of disorders that frequently require a wide range of chromosomal and genomic approaches for the diagnosis, management, and genetic counseling.神经发育障碍与智力残疾 接下来我们考虑另一类疾病，这类疾病常需广泛的染色体与基因组方法进行诊断、管理和遗传咨询。
Neurodevelopmental disorders are highly heterogeneous, encompassing impairments in cognition, communication, behavior, and motor functioning.神经发育障碍高度异质，包括认知、沟通、行为和运动功能方面的损伤。
Broadly considered, the category of neurodevelopmental disorders includes overlapping diagnoses such as intellectual disability (defined as impairment of cognitive and adaptive functions in childhood), autism spectrum disorder (ASD) (see Case 5), and attention-deficit hyperactivity disorder (ADHD).广义上，神经发育障碍类别包括重叠的诊断，如智力残疾（定义为儿童期认知和适应功能受损）、自闭症谱系障碍（见病例5）以及注意缺陷多动障碍。
This category can also include various neuropsychiatric conditions such as schizophrenia and bipolar disorder, complex traits of the type that are considered later in Chapter 9.此类别还可包括多种神经精神疾病，如精神分裂症和双相情感障碍，这类复杂性状将在第九章后续讨论。
The overall incidence of intellectual disability and developmental delay is estimated to be at least 2% to 3%, whereas ASD affects as many as 1%.智力残疾和发育迟缓的总发病率估计至少为2%至3%，而ASD的患病率高达1%。
Determining the genetic cause of intellectual disability in most patients is a particular challenge, especially in the absence of other clinical clues or information about the specific gene or region of the genome responsible.对大多数患者确定智力残疾的遗传原因尤其具有挑战性，尤其是在缺乏其他临床线索或关于特定基因或基因组区域信息的情况下。
Especially in sporadic cases without an obvious family history, a precise diagnosis can be helpful for clinical management and genetic counseling.尤其在无明显家族史的散发病例中，精确诊断有助于临床管理和遗传咨询。
Thus the full range of screening methods must be considered, including karyotyping and chromosomal microarrays, as well as whole exome and whole genome sequencing.因此，必须考虑全套筛查方法，包括核型分析、染色体微阵列，以及全外显子和全基因组测序。
Genomic Imbalance in Neurodevelopmental Disorders In large studies comparing diagnostic yield in this patient population, chromosomal microarray analysis detects pathogenic genomic imbalances in ~12% to 16% of cases, approximately fivefold more than G-banded karyotyping alone; on this basis, chromosomal microarrays are considered the first-tier clinical test to identify genomic imbalance in patients with unexplained intellectual disability or ASD.神经发育障碍中的基因组失衡 在比较该患者群体诊断产出的大型研究中，染色体微阵列分析检测到约12%至16%的病例存在致病性基因组失衡，比单独G显带核型分析高约五倍；基于此，染色体微阵列被视为识别不明原因智力残疾或ASD患者基因组失衡的一线临床检测。
Although an increase in the presence of multiple rare copy number variants is true both for intellectual disability and for ASD, the copy number variants in patients with intellectual disability tend to be larger and to encompass more genes and are more likely of de novo origin than those detected in ASD patients.尽管多重罕见拷贝数变异的存在在智力残疾和ASD中均有所增加，但智力残疾患者中的拷贝数变异往往更大、包含更多基因，且比ASD患者中检测到的更可能为新发变异。
Several deletion and duplication syndromes, including 3q29 deletion syndrome, 16p11. 2 deletion and duplication syndromes, and 22q11. 2 deletion and duplication syndromes, are associated with increased risk of neurodevelopmental and neuropsychiatric disorders.若干缺失和重复综合征，包括3q29缺失综合征、16p11.2缺失和重复综合征以及22q11.2缺失和重复综合征，与神经发育和神经精神疾病风险增加相关。
For instance, results from genome-wide analysis of rare copy number variants in 1123 ASD families showed a strong association between ASD and de novo 7q11. 23 duplications.例如，对1123个ASD家庭中罕见拷贝数变异进行全基因组分析的结果显示，ASD与新发7q11.23重复之间存在强关联。
Many hundreds of genes have been implicated to date, with estimates as high as a thousand or more genes in the genome that, when present in too few or too many copies, can lead to neurodevelopmental disorders.迄今已涉及数百个基因，估计基因组中多达一千个或更多基因在拷贝数过少或过多时可能导致神经发育障碍。
Although screening for the genomic imbalance due to copy number variants is accepted as a diagnostic tool, identifying individual genes and their pathogenic variants remains a significant challenge because of clinical and genetic heterogeneity.尽管筛查由拷贝数变异导致的基因组失衡已被接受为诊断工具，但由于临床和遗传异质性，鉴定单个基因及其致病性变异仍是一个重大挑战。
Some genes appear to be recurrent targets of variation, accounting for up to several percent of cases; exome sequencing can identify de novo coding variants with likely or proven pathogenicity in ~15% of patients with severe, sporadic nonsyndromic intellectual disability and in cohorts of patients with the diagnosis of ASD.某些基因似乎是变异的反复靶点，占病例的百分之几；外显子组测序可在约15%的重度、散发性非综合征型智力残疾患者以及诊断为ASD的患者队列中鉴定出可能或已证实致病的新发编码变异。
Whole genome sequencing has also identified likely pathogenic variants, either de novo or inherited, in ASD and in intellectual disability.全基因组测序也已鉴定出ASD和智力残疾中可能致病的新发或遗传变异。
Clinical Heterogeneity and Diagnostic Overlap A particular challenge for understanding neurodevelopmental disorders, their etiology, and their clinical course is the extraordinary degree of clinical heterogeneity, cooccurrence of symptoms, and diagnostic overlap among them.临床异质性与诊断重叠 理解神经发育障碍、其病因及临床病程的一大挑战是它们之间显著的临床异质性、症状共存及诊断重叠。
For cases due either to copy number variants or to single-gene variants, the same defect can lead to different clinical diagnoses in different cases and even in different family members—some with intellectual disability, some with ASD, and some with diagnosed psychiatric conditions.对于由拷贝数变异或单基因变异导致的病例，同一缺陷在不同病例甚至不同家族成员中可导致不同的临床诊断——有的为智力残疾，有的为ASD，有的为确诊的精神疾病。
This heterogeneity and overlap, even when categorized by genetic/genomic diagnosis rather than clinical diagnosis, suggests the need for further study of genotype/phenotype correlations to meaningfully capture the broad range of phenotypes that might emerge among individuals with the same genetic disorder.这种异质性和重叠，即使按遗传/基因组诊断而非临床诊断进行分类，也提示需要进一步研究基因型-表型相关性，以有意义地捕捉患有相同遗传病的个体可能出现的广泛表型范围。
One important factor is to analyze the effect of the copy number variant by comparing affected individuals to their unaffected family members (rather than to unrelated individuals in the general population), thus minimizing confounding effects of the wide range of cognitive and behavioral phenotypes observed even in the general population.一个重要因素是通过比较受影响个体与其未受影响的家庭成员（而非一般人群中的无关个体）来分析拷贝数变异的影响，从而尽量减少即使在一般人群中也能观察到的广泛认知和行为表型的混杂效应。
Mechanisms Causing Genomic Disorders NAHR This mechanism is also known as unequal crossing over that occurs between highly similar copies of SDs .导致基因组疾病的机制 NAHR 该机制也称为不等交换，发生在SD高度相似拷贝之间。
Direct copies can result in deletions or duplications, and inverted copies can result in inversions.直接拷贝可导致缺失或重复，反向拷贝可导致倒位。
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NAHR involves crossing over between two paralogous copies and can occur both in meiosis and mitosis at a lower frequency…
Ch6 — Segment 14
NAHR involves crossing over between two paralogous copies and can occur both in meiosis and mitosis at a lower frequency.NAHR涉及两个旁系同源拷贝之间的交叉互换，并且可以在减数分裂和有丝分裂中以较低频率发生。
The positions, homology, and size of the copies impact the rate of NAHR events.拷贝的位置、同源性和大小影响NAHR事件的发生率。
Regions of the genome that possess tandemly arranged SDs are more prone to rearrangements.具有串联排列SD（片段重复）的基因组区域更容易发生重排。
The rate of NAHR varies between SD pairs in the genome, ranging from 2. 32 × 10–5 to 8. 74 × 10–7.基因组中不同SD对之间的NAHR发生率不同，范围为2.32 × 10⁻⁵至8.74 × 10⁻⁷。
NHEJ This mechanism results in simple, blunt copy number variant endpoints that can have short homologies at the junctions (one to three nucleotides), and unlike NAHR, extensive sequence homology is not required .NHEJ 该机制产生简单、平末端的拷贝数变异端点，在连接处可能具有短同源性（一到三个核苷酸），且与NAHR不同，不需要广泛的序列同源性。
NHEJ can result in an aberrant repair and structural variation of the genome if ligation between double-strand breaks that are not a part of the same lesion occurs.如果不属于同一损伤的双链断裂之间发生连接，NHEJ可能导致异常修复和基因组结构变异。
It is possible to observe small deletions or the insertion of random nucleotides at the breakpoint junctions.在断点连接处可能观察到小缺失或随机核苷酸的插入。
NHEJ is error prone.NHEJ容易出错。
The breakpoints of SVs formed by NHEJ are frequently observed within mobile elements, such as SINEs and LINEs.由NHEJ形成的结构变异（SVs）的断点经常在转座元件（如SINE和LINE）内观察到。
MMBIR Replication-based repair mechanisms are important when single-strand breaks during the DNA replication process result in collapsed replication forks .MMBIR 基于复制的修复机制在DNA复制过程中单链断裂导致复制叉塌陷时非常重要。
Variants that occur as a result of this mechanism differ in size and sequence complexity.由该机制产生的变异在大小和序列复杂性上有所不同。
In addition to microhomology-mediated rearrangements, MMBIR mediated by inverted SDs and coupled with NHEJ can result in complex rearrangements with DUP-TRP/ INV-DUP.除了微同源介导的重排外，由反向SD介导并与NHEJ偶联的MMBIR可导致涉及DUP-TRP/INV-DUP的复杂重排。
DISORDERS ASSOCIATED WITH GENOMIC IMPRINTING For some disorders the expression of the disease phenotype depends on whether the mutant allele or abnormal chromosome has been inherited from the father or from the mother.与基因组印记相关的疾病 对于某些疾病，疾病表型的表达取决于突变等位基因或异常染色体是从父亲还是母亲遗传而来。
As we introduced in Chapter 3, such parentof-origin effects are the result of genomic imprinting.正如我们在第三章中介绍的，这种亲本起源效应是基因组印记的结果。
The effect of genomic imprinting on inheritance patterns in pedigrees will be discussed in Chapter 7.基因组印记对家系遗传模式的影响将在第七章讨论。
Here, we focus on the relevance of imprinting to clinical cytogenetics, as many imprinting effects come to light because of chromosome abnormalities.在此，我们重点关注印记与临床细胞遗传学的相关性，因为许多印记效应是由于染色体异常而显现的。
Evidence of genomic imprinting has been obtained for a number of chromosomes or chromosomal regions throughout the genome, as revealed by comparing phenotypes of individuals carrying the same cytogenetic abnormality affecting either the maternal or paternal homologue.通过比较携带影响母源或父源同源染色体的相同细胞遗传学异常的个体表型，已在整个基因组的多个染色体或染色体区域获得了基因组印记的证据。
Although estimates vary, it is likely that as many as several hundred genes in the human genome show imprinting effects.尽管估计值不一，但人类基因组中可能有多达数百个基因显示印记效应。
Some regions contain a single imprinted gene; others contain clusters of multiple imprinted genes, spanning in some cases well over 1 Mb along a chromosome.一些区域包含单个印记基因；其他区域包含多个印记基因的簇，在某些情况下沿染色体延伸超过1 Mb。
The hallmark of imprinted genes that distinguishes them from other autosomal loci is that only one allele, either maternal or paternal, is expressed in the relevant tissue.印记基因区别于其他常染色体位点的标志是，在相关组织中仅表达一个等位基因，即母源或父源等位基因。
The effect of such mechanisms on the clinical phenotype will necessarily depend on whether a variant (SNV and CNV) is present on the maternal or paternal homologue.此类机制对临床表型的影响必然取决于变异（SNV和CNV）存在于母源还是父源同源染色体上。
Among the best-studied examples of the role of genomic imprinting in human disease are PraderWilli syndrome (Case 38) and Angelman syndrome, and we discuss these next to illustrate the genetic and genomic features of imprinting conditions.基因组印记在人类疾病中作用的研究最充分的例子包括普拉德-威利综合征（病例38）和安吉尔曼综合征，接下来我们讨论这两种疾病以说明印记状况的遗传和基因组特征。
An additional example is Beckwith-Wiedemann syndrome.另一个例子是贝克威思-威德曼综合征。
Prader-Willi and Angelman Syndromes Prader-Willi syndrome is a relatively common syndrome characterized by neonatal hypotonia followed by obesity, excessive and indiscriminate eating habits, small hands and feet, short stature, hypogonadism, and intellectual disability .普拉德-威利综合征和安吉尔曼综合征 普拉德-威利综合征是一种相对常见的综合征，特征为新生儿肌张力低下，随后出现肥胖、过度且不加区分地进食、小手小脚、身材矮小、性腺功能减退和智力残疾。
Prader-Willi syndrome results from the absence of a paternally expressed imprinted gene or genes.普拉德-威利综合征是由于父源表达的一个或多个印记基因缺失所致。
In ~70% of cases of the syndrome there is a cytogenetic deletion of the proximal long arm of chromosome 15 (15q11. 2-q 13); the deletion is mediated by recombination involving SDs that flank a region of approximately 5 to 6 Mb and in that sense is mechanistically similar to other genomic disorders described earlier (see However, within this region lies a smaller interval that contains a number of monoallelically expressed genes, some of which are normally expressed only from the paternal copy and others of which are expressed only from the maternal copy.大约70%的该综合征病例存在染色体15近端长臂（15q11.2-q13）的细胞遗传学缺失；该缺失由涉及侧翼约5至6 Mb区域的SD重组介导，在此意义上其机制与前述其他基因组疾病相似（见……）。然而，在该区域内存在一个较小的区间，包含多个单等位基因表达的基因，其中一些通常仅从父源拷贝表达，另一些仅从母源拷贝表达。
In Prader-Willi syndrome, the deletion is found only on chromosome 15 inherited from the patient’s father ( Thus the genomes of these patients have genomic information in 15q11. 2-q 13 that derives only from their mothers, and the syndrome results from the loss of expression of one or more of the normally paternally expressed genes in the region.在普拉德-威利综合征中，缺失仅存在于从患者父亲遗传的染色体15上（因此这些患者的基因组在15q11.2-q13区域仅含有来自其母亲的基因组信息，该综合征是由于该区域中一个或多个通常父源表达的基因表达缺失所致。
Notably, the low-copy repeats that flank the PraderWilli and Angelman syndrome regions have also been implicated in other disorders, including duplication or triplication of the region or inverted duplication of chromosome 15.值得注意的是，侧翼于普拉德-威利和安吉尔曼综合征区域的低拷贝重复也与其他疾病有关，包括该区域的重复或三倍化，或染色体15的倒位重复。
This underscores that although imprinting is responsible for the inheritance and specific clinical findings in Prader-Willi and Angelman syndromes, the underlying mechanism of all these disorders involves unequal recombination of the SDs in the region.这强调了尽管印记是普拉德-威利和安吉尔曼综合征遗传和特定临床表现的原因，但这些疾病的基本机制均涉及该区域SD的不平等重组。
In contrast, in most patients with the rare Angelman syndrome, which is characterized by unusual facial appearance, short stature, severe intellectual disability, spasticity, and seizures, there is a deletion of the same chromosomal region, but now on the chromosome 15相反，在大多数罕见安吉尔曼综合征患者中（其特征为异常面容、身材矮小、严重智力残疾、痉挛和癫痫发作），存在相同染色体区域的缺失，但位于染色体15上。
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 93 inherited from the mother.
Ch6 — Segment 15
THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 93 inherited from the mother.疾病的染色体和基因组基础93遗传自母亲。
Patients with Angelman syndrome therefore have genetic information in 15q11. 2q 13 derived only from their fathers.因此，Angelman综合征患者在15q11.2-q13区域的遗传信息仅来自其父亲。
This unusual circumstance demonstrates strikingly that the parental origin of genetic material (in this case, in a segment of chromosome 15) can have a profound effect on the clinical expression of a defect.这种不寻常的情况显著地表明，遗传物质的亲本来源（在此例中为15号染色体的一段）可以对缺陷的临床表型产生深远影响。
Some patients with Prader-Willi syndrome do not have cytogenetically detectable deletions; instead, they have two cytogenetically normal chromosome 15s, both q 12 cen IC snoRNA gene cluster 15q11-13 deletions (PWS/AS) UBE3A PWS region (paternal AS region (maternal tel q 13. 2 q 14 q 15. 2 q 21. 1 q 21. 3 q 22. 2 q 22. 32 q 23 q 24. 2 q 25. 1 q 25. 3 q 26. 2 -4 -2 -1 0 +1 15 D C A B)) org) is represented by Jasper, whose smile reveals his widely spaced teeth and large lower jaw.一些Prader-Willi综合征患者没有细胞遗传学可检测的缺失；相反，他们拥有两条细胞遗传学正常的15号染色体，两者都包含q12着丝粒IC snoRNA基因簇15q11-13缺失（PWS/AS）UBE3A PWS区域（父源AS区域（母源端粒q13.2 q14 q15.2 q21.1 q21.3 q22.2 q22.32 q23 q24.2 q25.1 q25.3 q26.2 -4 -2 -1 0 +1 15 D C A B））org）由Jasper代表，他的微笑露出他的牙间距宽和大下颌。
(B) Prader-Willi syndrome (PWS) (pwsausa. org) is represented by Oaklyn, whose face shows almond-shaped eyes and narrow distance between the temple.(B) Prader-Willi综合征（PWS）（pwsausa.org）由Oaklyn代表，她的面部表现为杏仁状眼睛和窄的颞间距。
(C) Chromosomal microarray detection of ~5-Mb deletion in 15q11. 2-q 13. 1 (red).(C) 染色体微阵列检测到15q11.2-q13.1的约5 Mb缺失（红色）。
(D) Schematic of the 15q11. 2-q 13 region.(D) 15q11.2-q13区域的示意图。
The PWS region (shaded in blue) contains a series of imprinted genes (blue) that are expressed only from the paternal copy.PWS区域（蓝色阴影）包含一系列印记基因（蓝色），这些基因仅从父源拷贝表达。
The AS region (shaded in pink) contains two imprinted genes that are expressed only from the maternal copy, including the UBE3A gene, which is imprinted in the central nervous system, and variants in which can cause AS.AS区域（粉色阴影）包含两个印记基因，仅从母源拷贝表达，其中包括UBE3A基因，该基因在中枢神经系统中被印记，其变异可导致AS。
The region is flanked by nonimprinted genes (purple) that are expressed from both maternal and paternal copies.该区域两侧是非印记基因（紫色），从母源和父源拷贝均有表达。
Common deletions of the PWS/AS region, caused by recombination between pairs of segmental duplications, are shown in green at the bottom.由成对节段重复之间的重组引起的PWS/AS区域常见缺失，在底部以绿色显示。
Smaller deletions of the imprinting center (IC; orange) and of a subset of genes in the small nucleolar RNA (snoRNA) gene cluster can also lead to PWS. cen, Centromere; tel, telomere.印记中心（IC；橙色）和小核仁RNA（snoRNA）基因簇中部分基因的更小缺失也可导致PWS。cen，着丝粒；tel，端粒。
(Photograph by Rick Guidotti, Positive Exposure, www. positiveexposure. org; C, courtesy M.（照片由Rick Guidotti拍摄，Positive Exposure，www.positiveexposure.org；C图由佐治亚州亚特兰大埃默里遗传学实验室的M. Katharine Rudd提供；D图修改自Gene Reviews。）
Katharine Rudd, Emory Genetics Laboratory, Atlanta, Georgia; D, modified from Gene Reviews.可从www.ncbi.nlm.nih.gov/books/NBK1116/获取。
Available from www. ncbi. nlm. nih. gov/books/NBK1116/.版权©华盛顿大学。）
Copyright © University of Washington.)[TL:missing]
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of which were inherited from the mother (see This situation illustrates uniparental disomy, introduced previously in thi…
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of which were inherited from the mother (see This situation illustrates uniparental disomy, introduced previously in this chapter in the section on abnormal chromosome segregation.其中来自母方遗传（参见本节前文关于异常染色体分离部分中介绍的单亲二体情况）。
A smaller percentage of patients with Angelman syndrome also have uniparental disomy, but in their case, with two intact chromosome 15s of paternal origin (see These patients add further emphasis that, although genomic imprinting is responsible for bringing such cases to clinical attention, the underlying defect in a proportion of cases is one of chromosome segregation, not one of imprinting per se, which is completely normal in these cases.较小比例的Angelman综合征患者也存在单亲二体，但他们的病例中，两条完整的15号染色体均来自父方（参见这些患者进一步强调，尽管基因组印记导致此类病例受到临床关注，但其中部分病例的根本缺陷是染色体分离异常，而非印记本身的问题，在这些病例中印记是完全正常的）。
Primary defects in the imprinting process are seen, however, in a few patients with Prader-Willi syndrome and Angelman syndrome, who have abnormalities in the imprinting center itself.然而，在少数Prader-Willi综合征和Angelman综合征患者中可见印记过程的原发性缺陷，这些患者的印记中心本身存在异常。
As a result, the switch from female to male imprinting during spermatogenesis or from male to female imprinting during oogenesis fails to occur.因此，在精子发生过程中从女性印记向男性印记的转换，或在卵子发生过程中从男性印记向女性印记的转换未能发生。
Fertilization by a sperm carrying an abnormally persistent female imprint would produce a child with Prader-Willi syndrome; fertilization of an egg that bears an inappropriately persistent male imprint would result in Angelman syndrome (see There is evidence that the major features of the Prader-Willi and Angelman syndrome phenotypes can be accounted for by defects at particular genes within the imprinted region.携带异常持续存在女性印记的精子受精后会产生患有Prader-Willi综合征的儿童；携带不适当持续存在男性印记的卵子受精后会导致Angelman综合征（参见有证据表明，Prader-Willi综合征和Angelman综合征表型的主要特征可由印记区域内特定基因的缺陷来解释）。
Variants in the maternal copy of a single gene, the ubiquitin-protein ligase E3A gene (UBE3A), have been found to cause Angelman syndrome (see The UBE3A gene is located within the 15q11. 2-q 13 imprinted region and is normally expressed only from the maternal allele in the central nervous system.已发现单个基因——泛素蛋白连接酶E3A基因（UBE3A）的母方拷贝变异可导致Angelman综合征（参见UBE3A基因位于15q11.2-q13印记区域内，在中枢神经系统中通常仅从母方等位基因表达）。
Maternally inherited single-gene variants in UBE3A account for ~10% of Angelman syndrome cases.UBE3A中母方遗传的单基因变异约占Angelman综合征病例的10%。
In Prader-Willi syndrome, several patients have been described with deletions of a much smaller region on the paternally inherited chromosome 15, specifically implicating the noncoding small nucleolar RNA (snoRNA)116 gene cluster in the etiology of the syndrome.在Prader-Willi综合征中，已有数例患者描述为父方遗传的15号染色体上更小区域的缺失，特别提示非编码小核仁RNA（snoRNA）116基因簇与该综合征的病因相关。
THE SEX CHROMOSOMES AND THEIR ABNORMALITIES The X and Y chromosomes have long attracted interest because they differ between the sexes, have their own specific patterns of inheritance, and are involved in primary sex determination.性染色体及其异常 X和Y染色体长期以来一直引起人们的兴趣，因为它们在两性之间不同，具有自身特定的遗传模式，并参与初级性别决定。
They are structurally ­distinct and subject to different forms of genetic regulation, yet they pair in male meiosis.它们在结构上不同，并受到不同形式的遗传调控，但在男性减数分裂中配对。
For all these reasons they require special attention.由于所有这些原因，它们需要特别关注。
In this section we review the structure of the sex chromosomes, control of the sex determination, and abnormalities of sex development.在本节中，我们回顾性染色体的结构、性别决定的调控以及性发育异常。
The Structure of the Sex Chromosomes The X Chromosome One of the chromosomes involved in sex determination is the X chromosome.性染色体的结构 X染色体 参与性别决定的染色体之一是X染色体。
In 2020, the first telomere-to-telomere assembly of X was finished.2020年，完成了第一条X染色体的端粒到端粒组装。
There are ~900 genes, many of which are only found on the X.约有900个基因，其中许多仅存在于X染色体上。
However, genes in pseudoautosomal regions are found on both the X and Y.然而，位于假常染色体区域的基因在X和Y染色体上均存在。
Males are usually affected by X-linked diseases, e. g.男性通常受X连锁疾病影响，例如
Ornithine transcarbamylase deficiency .鸟氨酸氨甲酰转移酶缺乏症。
Due to X-inactivation, X-linked traits, may appear differently in males and females.由于X失活，X连锁性状在男性和女性中可能表现不同。
X Chromosome Inactivation The principle of X inactivation is that in somatic cells in normal females (but not in normal males), one X chromosome is inactivated early in development, thus equalizing the expression of X-linked genes in the two sexes (see Chapter 3).X染色体失活 X失活的原则是，在正常女性（而非正常男性）的体细胞中，一条X染色体在发育早期失活，从而使两性中X连锁基因的表达均等化（见第3章）。
In normal female development, because the choice of which X chromosome is to be inactivated is a random one that is then maintained clonally, females are mosaic with respect to X-linked gene expression .在正常女性发育过程中，由于哪条X染色体失活的选择是随机的，随后克隆性维持，因此女性在X连锁基因表达方面呈嵌合状态。
There are many epigenetic features, including gene expression, chromatin state, noncoding RNA, DNA replication timing, histone variants, and histone modifications, that distinguish the active and inactive X chromosomes in somatic cells ( These features can be useful diagnostically for identifying the inactive X chromosome(s) in clinical material.存在许多表观遗传特征，包括基因表达、染色质状态、非编码RNA、DNA复制时序、组蛋白变体和组蛋白修饰，这些特征区分体细胞中的活性X染色体和失活X染色体（这些特征在临床材料中识别失活X染色体时具有诊断价值）。
In patients with extra X chromosomes (whether male or female), any X chromosome in excess of one is inactivated.在具有额外X染色体（无论男性或女性）的患者中，任何超过一条的X染色体均被失活。
Thus all diploid somatic cells in both males and females have a single active X chromosome, regardless of the total number of X or Y chromosomes present.因此，无论存在多少条X或Y染色体，男性和女性中的所有二倍体体细胞均只有一条活性X染色体。
The X chromosome contains ~900 genes, but not all of these are subject to inactivation.X染色体含有约900个基因，但并非所有基因都受到失活影响。
Notably, the genes that continue to be expressed, at least to some degree, 2-q 13 deletion ≈70–75% (paternal) ≈75% (maternal) Uniparental disomy ≈25–30% (maternal) ≈1–2% (paternal) Imprinting defects (without an imprinting centre deletion) ≈1% ≈3% Imprinting centre deletion ≈10–15% of patients with an imprinting defect ≈10–15% of patients with an imprinting defect Gene variants Rare (small deletions within snoRNA gene cluster) ≈5–10% (UBE3A variants) Unidentified &lt;1% ≈10–15% snoRNA, Small nucleolar RNA.值得注意的是，至少在一定程度上继续表达的基因，2-q13缺失约70–75%（父方）约75%（母方）单亲二体约25–30%（母方）约1–2%（父方）印记缺陷（无印记中心缺失）约1%约3%印记中心缺失约10–15%的印记缺陷患者约10–15%的印记缺陷患者基因变异罕见（snoRNA基因簇内小缺失）约5–10%（UBE3A变异）未明确<1%约10–15% snoRNA，小核仁RNA。
Data from Beygo J, Buiting K, Ramsden SC, et al: Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes, Eur J Hum Genet 27:1326–1340, 2019.数据来源于Beygo J, Buiting K, Ramsden SC, 等: EMQN/ACGS关于Prader-Willi和Angelman综合征分子分析最佳实践指南的更新, Eur J Hum Genet 27:1326–1340, 2019。
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 95 Ichthyosis, X-linked Placental steroid sulfatase deficiency Kallmann syn…
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 95 Ichthyosis, X-linked Placental steroid sulfatase deficiency Kallmann syndrome Chondrodysplasia punctata, X-linked recessive Hypophosphatemia Aicardi syndrome Hypomagnesemia, X-linked Retinoschisis Adrenal hypoplasia Glycerol kinase deficiency Duchenne muscular dystrophy (DMD) Becker muscular dystrophy (BMD) Ornithine transcarbamylase (OTC) deficiency Norrie disease Retinitis pigmentosa-2 Alport-like hereditary nephritis Allelic disorders 13 12. 2 12. 1 11 11. 1 11. 21 11. 22 11. 23 11. 3 11. 4 21. 1 21. 2 p q 21. 3 22. 1 22. 2 22. 3 21. 1 21. 2 21. 3 22. 1 22. 2 22. 3 23 24 25 26 27 28 , E18–E33, 2010; review is available: Migeon BR: X-linked diseases: susceptible females, Genet Med 22:1156–1174, 2020.) from the inactive X are not distributed randomly along the X chromosome; many more genes “escape” inactivation on distal Xp (as many as 50%) than on Xq (just a few percent).来自失活X染色体的基因并非沿X染色体随机分布；在远端Xp上逃避失活的基因（多达50%）远多于Xq（仅百分之几）。
This finding has important implications for genetic counseling in cases of a partial X chromosome aneuploidy because imbalance for genes on Xp may have greater clinical significance than imbalance for genes on Xq, where the effect is largely mitigated by X inactivation.这一发现对部分X染色体非整倍体病例的遗传咨询具有重要意义，因为Xp上基因的失衡可能比Xq上基因的失衡具有更大的临床意义，而Xq上的效应主要通过X失活得以减轻。
Patterns of X Inactivation.X失活模式。
X inactivation is normally random in female somatic cells and leads to mosaicism for two cell populations expressing alleles from one or the other X.X失活在女性体细胞中通常是随机的，导致两个细胞群体的嵌合现象，分别表达来自其中一个X染色体的等位基因。
Where examined, most females have approximately equal proportions of cells expressing alleles from the maternal or paternal X (i. e., ~50:50), and ~90% of phenotypically normal females fall within a distribution that extends from ~25:75 to ~75:25 .在已检查的个体中，大多数女性的细胞中表达母系或父系X等位基因的比例大致相等（即约50:50），约90%的表型正常女性分布于约25:75至75:25的范围内。
Such a distribution presumably reflects the这样的分布可能反映了
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expected range of outcomes for a random event (i. e., the choice of which X will be the inactive X) involving a relative…
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expected range of outcomes for a random event (i. e., the choice of which X will be the inactive X) involving a relatively small number of cells during early embryogenesis.涉及早期胚胎发生过程中相对少量细胞的随机事件（即选择哪个X成为失活X）的预期结果范围。
For individuals who are carriers for X-linked single-gene disorders (see Chapter 7), this X inactivation ratio can influence the clinical phenotype, depending on what proportion of cells in relevant tissues or cell types express the deleterious allele on the active X. 46,XX Nonrandom inactivation of abnormal X Abnormal X Nonrandom inactivation of normal X Balanced Nonrandom inactivation of der(X) Unbalanced X; autosome translocations X Xi Xi X X Xi abn X X Xi der(X) der(A) X Xi der(X) 90% of females Proportion of females 0. 10 0. 05 0. 00 95:5 75:25 50:50 25:75 5:95 X inactivation ratio A B Normal female cells (46,XX) undergo random X inactivation, resulting in a mosaic of two cell populations (left) in which either the paternal or maternal X is the inactive X (Xi, indicated by shaded box).对于X连锁单基因疾病（见第7章）携带者个体，此X失活比率可影响临床表型，具体取决于相关组织或细胞类型中活性X表达有害等位基因的细胞比例。46,XX 非随机失活 异常X 异常X 非随机失活 正常X 平衡 非随机失活 der(X) 不平衡 X;常染色体易位 X Xi Xi X X Xi abn X X Xi der(X) der(A) X Xi der(X) 90%女性 女性比例 0.10 0.05 0.00 95:5 75:25 50:50 25:75 5:95 X失活比率 A B 正常女性细胞(46,XX)经历随机X失活，产生两个细胞群体的嵌合体（左），其中父源或母源X为失活X（Xi，以阴影框表示）。
In phenotypically normal females, the ratio of the two cell populations has a mode at 50:50, but with variation observed in the population (right), some with an excess of cells expressing alleles from the paternal X and others with an excess of cells expressing alleles from the maternal X.在表型正常的女性中，两个细胞群体的比率众数为50:50，但人群中观察到变异（右），部分细胞过多表达父源X的等位基因，另一部分细胞过多表达母源X的等位基因。
(B) Individuals carrying a structurally abnormal X (abn X) or X;autosome translocation in a balanced or unbalanced state show nonrandom X inactivation in which virtually all cells have the same X inactive.(B) 携带结构异常X（abn X）或处于平衡或不平衡状态下的X;常染色体易位的个体显示非随机X失活，其中几乎所有细胞具有相同的失活X。
The other cell population is inviable or at a growth disadvantage because of genetic imbalance and is thus underrepresented or absent. der(X) and der(A) represent the two derivatives of the X;autosome translocation.另一个细胞群体因遗传失衡而不可存活或处于生长劣势，因此代表不足或缺失。der(X)和der(A)代表X;常染色体易位的两个衍生染色体。
(B, Data from AmosLandfraf JM, Cottle A, Plenge RM, et al: X chromosome inactivation patterns of 1005 phenotypically unaffected females, Am J Hum Genet 79:493–499, 2006; review is available: Fang H, Disteche CM, Berletch JB: X inactivation and escape: epigenetic and structural features, Front Cell Dev Biol 219, 2019.)(B, 数据来自Amos-Landgraf JM, Cottle A, Plenge RM, 等: X chromosome inactivation patterns of 1005 phenotypically unaffected females, Am J Hum Genet 79:493–499, 2006; 综述可见: Fang H, Disteche CM, Berletch JB: X inactivation and escape: epigenetic and structural features, Front Cell Dev Biol 219, 2019.)
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 97 However, there are exceptions to the distribution expected for random X inactivation when the karyotype involves a structurally abnormal X chromosome.染色体与基因组疾病的基础 97 然而，当核型涉及结构异常的X染色体时，随机X失活的预期分布存在例外。
For example, in nearly all patients with unbalanced structural abnormalities of an X chromosome (including deletions, duplications, and isochromosomes), the structurally abnormal chromosome is always the inactive X.例如，在几乎所有携带X染色体非平衡结构异常（包括缺失、重复和等臂染色体）的患者中，结构异常的染色体总是失活的X染色体。
Because the initial inactivation event early in embryonic development is likely random, the patterns observed after birth probably reflect secondary selection against genetically unbalanced cells that are invisible .由于胚胎发育早期的初始失活事件可能是随机的，出生后观察到的模式可能反映了对遗传上不平衡但不可见的细胞的继发性选择。
Because of this preferential inactivation of the abnormal X, such X chromosome anomalies have less of an impact on phenotype than unbalanced abnormalities of similar size or gene content involving autosomes.由于这种异常X的优先失活，此类X染色体异常对表型的影响小于涉及常染色体的相似大小或基因含量的非平衡异常。
Nonrandom inactivation is also observed in most cases of X;autosome translocations .在大多数X；常染色体易位病例中也观察到非随机失活。
If such a translocation is balanced, the normal X chromosome is preferentially inactivated, and the two parts of the translocated chromosome remain active, again likely reflecting selection against cells in which critical autosomal genes have been inactivated.如果此类易位是平衡的，则正常X染色体被优先失活，而易位染色体的两个部分保持活性，这同样可能反映了对关键常染色体基因被失活的细胞的选择。
In the unbalanced offspring of a balanced carrier, however, only the translocation product carrying the X inactivation center is present, and this chromosome is invariably inactivated; the normal X is always active.然而，在平衡携带者的非平衡后代中，仅存在携带X失活中心的易位产物，且该染色体总是被失活；正常X始终保持活性。
These nonrandom patterns of inactivation have the general effect of minimizing, but not always eliminating, the clinical consequences of the particular chromosomal defect.这些非随机失活模式具有减轻（但并非总是消除）特定染色体缺陷临床后果的一般作用。
Because patterns of X inactivation are strongly correlated with clinical outcome, determination of an individual’s X inactivation pattern by cytologic or molecular analysis (see The X Inactivation Center.由于X失活模式与临床结局密切相关，通过细胞学或分子分析（参见X失活中心）确定个体的X失活模式具有重要意义。
Inactivation of an X chromosome depends on the presence of the X inactivation center region (XIC) on that chromosome, whether it is a normal X chromosome or a structurally abnormal X (see Chapter 3).X染色体的失活依赖于该染色体上X失活中心区域（XIC）的存在，无论该染色体是正常X染色体还是结构异常的X染色体（参见第3章）。
Detailed analysis of structurally abnormal, inactivated X chromosomes led to the identification of the XIC within an ~800-kb candidate region in proximal Xq, in band Xq 13. 2 , which coordinates many, if not all, of the critical steps necessary to initiate and promulgate the silenced chromatin state along the near-entirety of the X chosen to become the inactive X.对结构异常且失活的X染色体的详细分析，使XIC被定位于近端Xq的约800 kb候选区域内，即Xq13.2带，该区域协调启动和传播沿被选为失活X的整条染色体近乎全长的沉默染色质状态所需的关键步骤（即使不是全部）。
As introduced in Chapter 3, this complex series of events requires a noncoding RNA gene, XIST, that appears to be a key master regulatory locus for the onset of X inactivation.如第3章所述，这一系列复杂事件需要一个非编码RNA基因XIST，它似乎是启动X失活的关键主调控基因座。
Two additional noncoding RNA genes, DXZ4 and FIRRE are in the interval and have been implicated in various aspects of the development and maintenance of XIC.另外两个非编码RNA基因DXZ4和FIRRE位于该区间，并被认为参与XIC发育和维持的多个方面。
X-Linked Intellectual Disability A long-appreciated aspect of intellectual disability is the excess of males in the affected population, and a large number of variants, microdeletions, or duplications causing X-linked intellectual disability have been documented.X连锁智力障碍 智力障碍中一个长期被认识的特征是受累人群男性过多，已有大量导致X连锁智力障碍的变异、微缺失或重复被记录。
The collective incidence of such X-linked defects has been estimated to be as high as 1 in 500 to 1000 live births.此类X连锁缺陷的总发病率估计高达每500至1000例活产儿中1例。
The most common cause of X-linked intellectual disability is a variant in the FMR1 gene in males with fragile X syndrome (Case 17).X连锁智力障碍最常见的原因是男性脆性X综合征（病例17）患者中FMR1基因的变异。
However, nearly 100 other X-linked genes have been implicated in X-linked intellectual disability, mostly on the basis of large family studies.然而，已有近100个其他X连锁基因被认为与X连锁智力障碍相关，主要基于大型家系研究。
Chromosomal microarray analysis has identified presumptive causal copy number variants and insertion-deletions in a further 10% of such families.染色体微阵列分析已在另外10%的此类家系中鉴定出推定致病的拷贝数变异及插入缺失。
In addition, exome sequencing efforts summarized in the preceding section to identify de novo changes in patients with intellectual disability have revealed an excess of such variants on the X chromosome.此外，前文概述的通过外显子组测序在智力障碍患者中鉴定新生改变的研究，揭示了X染色体上此类变异的富集。
The Y Chromosome The structure of the Y chromosome and its role in sex development has been determined at both the molecular and genomic levels .Y染色体 Y染色体的结构及其在性别发育中的作用已在分子和基因组水平得到明确。
In male meiosis, the X and Y chromosomes normally pair by segments at the ends of their short arms (see Chapter 2) and undergo recombination in that region.在男性减数分裂中，X和Y染色体通常通过其短臂末端的区段配对（参见第2章）并在该区域发生重组。
The pairing segment includes the pseudoautosomal region of the X and Y chromosomes, so-called because the X- and Y-linked copies of this region are essentially identical to one another and undergo homologous recombination in meiosis I, like pairs of autosomes.配对区段包括X和Y染色体的假常染色体区，之所以如此命名，是因为该区域的X连锁和Y连锁拷贝彼此基本一致，并在减数分裂I中像常染色体对一样发生同源重组。
(A second, smaller pseudoautosomal segment is located at the distal ends of Xq and Yq [ By comparison with autosomes and the X chromosome, the Y chromosome is relatively gene poor and contains fewer than 100 genes (some of which belong to multigene families), specifying only ~2 dozen distinct proteins.（第二个较小的假常染色体区段位于Xq和Yq的远端末端。）与常染色体和X染色体相比，Y染色体基因相对贫乏，包含少于100个基因（其中一些属于多基因家族），仅编码约24种不同的蛋白质。
Notably, the functions of a high proportion of these genes are restricted to gonadal and genital development.值得注意的是，这些基因中很大一部分的功能局限于性腺和生殖器发育。
Near the pseudoautosomal boundary on the Y chromosome lies the SRY gene (sex-determining region on the Y).在Y染色体的假常染色体边界附近存在SRY基因（Y染色体上的性别决定区）。
It is present in many males with an otherwise normal 46,XX karyotype and is deleted or mutated in a proportion of females with an otherwise normal 46,XY karyotype, thus strongly implicating SRY in normal male sex determination.该基因存在于许多核型为46,XX的正常男性中，并在部分核型为46,XY的正常女性中缺失或突变，从而强烈表明SRY在正常男性性别决定中发挥作用。
SRY is expressed only briefly early in development in cells of the germinal ridge just before differentiation of the testis.SRY仅在胚胎发育早期、睾丸分化前生殖嵴细胞中短暂表达。
SRY encodes a DNAbinding protein that is likely to be a transcription factor, which up-regulates a key autosomal gene, SOX9, in the ambipotent gonad, leading ultimately to testes differentiation.SRY编码一种DNA结合蛋白，很可能是一种转录因子，在双向潜能性腺中上调关键常染色体基因SOX9，最终导致睾丸分化。
Although there is clear evidence demonstrating the critical role of SRY in normal male sexual development, the presence or absence of SRY does not explain all cases of abnormal sex determination.尽管有明确证据表明SRY在正常男性性发育中的关键作用，但SRY的存在或缺失并不能解释所有性别决定异常病例。
Other genes are involved in the sex determination pathway and are discussed later in this chapter.其他基因参与性别决定通路，将在本章后续讨论。
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One or more genes on the long arm of the Y chromosome appear to be important for spermatogenesis because deletions of th…
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One or more genes on the long arm of the Y chromosome appear to be important for spermatogenesis because deletions of these regions, AZFa, AZFb, and AZFc, termed azoospermia factors (AZF), lead to low sperm count, ranging from cases of nonobstructive azoospermia (no sperm detectable in semen) to severe oligospermia (&lt;5 million/m L; normal range, 20–40 million/m L).Y染色体长臂上的一个或多个基因似乎对精子发生至关重要，因为这些区域（AZFa、AZFb和AZFc）的缺失（称为无精子症因子（AZF））会导致精子数量减少，范围从非梗阻性无精子症（精液中检测不到精子）到严重少精子症（<5百万/毫升；正常范围20–40百万/毫升）。
De novo deletions of AZFc arise in ~1 in 4000 males and account for ~12% of azoospermic males and ~6% of males with severe oligospermia.AZFc的新生缺失发生率约为1/4000男性，约占无精子症男性的12%和严重少精子症男性的6%。
The Control of Sex Determination The process of sex determination can be thought of as occurring in distinct but interrelated steps: Establishment of chromosomal sex (i. e., XY or XX) at the time of fertilization Initiation of alternate pathways to differentiation of one or the other gonadal sex, as determined normally by the presence or absence of the testis-determining gene (SRY) Continuation of sex-specific differentiation of internal and external sexual organs Especially after puberty, development of distinctive secondary sexual characteristics to create the corresponding phenotypic sex, as a male or female Whereas the sex chromosomes play a determining role in specifying chromosomal and gonadal sex, a number of genes located on both the sex chromosomes and the autosomes are involved in sex determination and subsequent sexual differentiation.性别决定的控制可以认为发生在不同但相互关联的步骤：受精时染色体性别（即XY或XX）的建立；由睾丸决定基因（SRY）存在与否决定的向一种或另一种性腺性别分化的交替途径的启动；内外性器官性别特异性分化的延续；特别是在青春期后，发展出独特的第二性征以形成相应的表型性别（男性或女性）；尽管性染色体在指定染色体性别和性腺性别中起决定性作用，但位于性染色体和常染色体上的许多基因也参与性别决定及随后的性分化。
In most instances, the role of these genes has come to light as a result of patients with various conditions known as disorders of sex development (DSD), and many of these are discussed later in this chapter.在大多数情况下，这些基因的作用是通过患有各种称为性发育异常（DSD）的患者而得以揭示，其中许多将在本章后面讨论。
XIC Normal X (with XIC) Abnormal X (XIC absent) X inactivation XIST ncRNA from Xi Spreading along Xi Epigenetic silencing of most genes on Xi Monoallelic gene expression Biallelic gene expression No X inactivation Xi A B On normal X chromosomes, XIC lies within an ~800-kb candidate region in Xq 13. 2 that contains a number of noncoding RNA (ncRNA) genes, including XIST, the master X inactivation control gene.XIC（正常X带有XIC，异常X缺失XIC）、X失活、来自Xi的XIST ncRNA、沿Xi扩散、Xi上大多数基因的表观遗传沉默、单等位基因表达、双等位基因表达、无X失活、Xi A B，在正常X染色体上，XIC位于Xq13.2的一个约800-kb候选区域内，该区域包含许多非编码RNA（ncRNA）基因，包括XIST——主要的X失活控制基因。
In early development in XX embryos, the XIST RNA spreads along the length of one X, which will become the inactive X (Xi), with epigenetic silencing of most genes on that X chromosome, resulting in monoallelic expression of most, but not all X-linked genes.在XX胚胎的早期发育中，XIST RNA沿一条X染色体的长度扩散，该染色体将成为失活X（Xi），并导致该X染色体上大多数基因的表观遗传沉默，从而使得大多数（但非全部）X连锁基因表现为单等位基因表达。
(B) On structurally abnormal X chromosomes that lack the XIC, X inactivation cannot occur and genes present on the abnormal X are expressed biallelically.(B) 在缺乏XIC的结构异常X染色体上，X失活不能发生，异常X上的基因呈双等位基因表达。
Although a fairly large abnormal X is shown here for illustrative purposes, in fact only very small such fragments are observed in female patients, who invariably display significant congenital anomalies, suggesting that biallelic expression of larger numbers of X-linked genes is inconsistent with normal development and is likely inviable.尽管这里为了说明目的显示了一个相当大的异常X染色体，但实际上在女性患者中只观察到非常小的此类片段，这些患者无一例外地表现出显著的先天性异常，这表明大量X连锁基因的双等位基因表达与正常发育不相容，并且很可能无法存活。
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 99 Embryology of the Reproductive System By the sixth week of development i…
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 99 Embryology of the Reproductive System By the sixth week of development in both sexes, the primordial germ cells have migrated from their earlier extraembryonic location to the paired genital ridges, where they are surrounded by the sex cords to form a pair of primitive gonads.疾病的染色体和基因组基础 99 生殖系统胚胎学 到发育的第六周，两性的原始生殖细胞已从其早期的胚胎外位置迁移至成对的生殖嵴，在那里被性索包围，形成一对原始性腺。
Up to this time, the developing gonad is ambipotent, regardless of whether it is chromosomally XX or XY .在此之前，发育中的性腺是双能的，无论其染色体是XX还是XY。
Development into an ovary or a testis is determined by the coordinated action of a sequence of genes in finely balanced pathways that lead to ovarian development when no Y chromosome is present but tip to the side of testicular development when a Y is present.发育成卵巢或睾丸由一系列基因在精细平衡通路中的协同作用决定，当不存在Y染色体时，该通路导向卵巢发育，但当存在Y染色体时，则偏向睾丸发育。
Under normal circumstances, the ovarian pathway is followed unless the SRY gene diverts development into the male pathway.正常情况下，卵巢通路被遵循，除非SRY基因将发育转向男性通路。
In the absence of the SRY gene, the gonad begins to differentiate to form an ovary, beginning as early as the eighth week of gestation and continuing for several weeks; the cortex develops, the medulla regresses, and oogonia begin to develop within follicles .在缺乏SRY基因的情况下，性腺开始分化形成卵巢，最早始于妊娠第8周并持续数周；皮质发育，髓质退化，卵原细胞开始在卵泡内发育。
Beginning at approximately the third month, the oogonia enter meiosis I, but (as described in Chapter 2) this process is arrested at dictyotene until ovulation occurs many years later.大约从第3个月开始，卵原细胞进入减数第一次分裂，但（如第2章所述）此过程停滞于双线期，直至多年后排卵发生。
In the presence of the SRY gene, however, the medullary tissue forms typical testes with seminiferous tubules and Leydig cells that, under the stimulation of chorionic gonadotropin from the placenta, become capable of androgen secretion .然而，在SRY基因存在的情况下，髓质组织形成典型的睾丸，内含生精小管和间质细胞，这些细胞在胎盘绒毛膜促性腺激素的刺激下，能够分泌雄激素。
Spermatogonia, derived from the primordial germ cells by successive mitoses, line the walls of the seminiferous tubules where they reside together with supporting Sertoli cells, awaiting the onset of puberty to begin spermatogenesis.精原细胞由原始生殖细胞经连续有丝分裂衍生而来，排列在生精小管壁上，与支持性支持细胞共同定居，等待青春期开始以启动精子发生。
In the early embryo, the external genitalia consist of a genital tubercle, paired labioscrotal swellings, and paired urethral folds.在早期胚胎中，外生殖器由生殖结节、成对的阴唇阴囊隆起和成对的尿道褶组成。
From this undifferentiated state, male external genitalia develop under the influence of androgens, beginning at around 12 weeks of gestation.从这种未分化状态开始，男性外生殖器在雄激素的影响下发育，约始于妊娠第12周。
In the absence of a testis (or, more specifically, in the absence of androgens), female external genitalia are formed regardless of whether an ovary is present.缺乏睾丸时（或更具体地说，缺乏雄激素时），无论是否存在卵巢，都会形成女性外生殖器。
Sex Chromosomal Aneuploidy and Aberration The most common sex chromosome abnormalities involve aneuploidy for the X and/or Y chromosomes.性染色体非整倍性与畸变 最常见的性染色体异常涉及X和/或Y染色体的非整倍性。
The phenotypes associated with these chromosomal defects are, in general, less severe than those associated with comparable autosomal disorders because, as discussed earlier, X chromosome inactivation, as well as the low gene content of the Y, minimize the clinical consequences of sex chromosome imbalance.与这些染色体缺陷相关的表型通常比类似常染色体疾病引起的表型轻，因为如前所述，X染色体失活以及Y染色体基因含量低，最大限度地减少了性染色体失衡的临床后果。
By far the most common sex chromosome defects in liveborn infants and in fetuses are the trisomic types (XXY, XXX, and XYY), but all three are rare in spontaneous abortions.迄今为止，活产婴儿和胎儿中最常见的性染色体缺陷是三体型（XXY、XXX和XYY），但这三种类型在自然流产中均罕见。
For instance, the incidence of Klinefelter syndrome (XXY) is estimated to be 1 in 650 male births, the incidence of triple X syndrome (XXX) is estimated to be 1 in 1000 females, and the incidence rate of XYY syndrome is p q SRY region present in XX testicular DSD region deleted in XY gonadal dysgenesis regions deleted in azoospermia USP9Y DDX3Y AZFa DAZ genes AZFc AZFb 11. 3 11. 2 11. 21 11. 22 11. 23 12 Centromere Yp pseudoautosomal region Yq pseudoautosomal region Heterochromatic region Individual genes and regions implicated in sex determination, DSDs, and defects of spermatogenesis are indicated, as discussed in the text.例如，克兰费尔特综合征（XXY）的发病率估计为每650名男性出生中1例，三X综合征（XXX）的发病率估计为每1000名女性中1例，而XYY综合征的发病率是p q SRY区（存在于XX睾丸型DSD中）、区（缺失于XY性腺发育不全中）、区（缺失于无精子症中）USP9Y DDX3Y AZFa DAZ基因 AZFc AZFb 11.3 11.2 11.21 11.22 11.23 12 着丝粒 Yp假常染色体区 Yq假常染色体区 异染色质区 与性别决定、DSDs及精子发生缺陷相关的单个基因和区域如图所示，文中已讨论。
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1 in 1000 males ( In contrast, monosomy for the X (Turner syndrome Case 47) is less frequent in liveborn infants but is …
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1 in 1000 males ( In contrast, monosomy for the X (Turner syndrome Case 47) is less frequent in liveborn infants but is the most common chromosome anomaly reported in spontaneous abortions (see 2).每1000名男性中有1例（相比之下，X单体型（特纳综合征病例47）在活产婴儿中较少见，但在自然流产中是最常见的染色体异常（见2）。
Klinefelter Syndrome (47,XXY).克氏综合征（47,XXY）。
The incidence of Klinefelter syndrome Testis Ovary (AZF genes) Paramesonephric duct Mesonephric duct Y chromosome present Y chromosome absent Spermatogenesis Female internal/external genitalia Male internal/external genitalia Androgens See text for discussion.克氏综合征的发生率、睾丸、卵巢（AZF基因）、副中肾管、中肾管、Y染色体存在、Y染色体缺失、精子发生、女性内/外生殖器、男性内/外生殖器、雄激素——详见正文讨论。
Data updated from Robinson A, Linden MG, Bender BG: Prenatal diagnosis of sex chromosome abnormalities.数据更新自Robinson A, Linden MG, Bender BG: 性染色体异常的产前诊断。
In Milunsky A, ed: Genetic disorders of the fetus, ed 4, Baltimore, 1998, Johns Hopkins University Press, pp 249–285; Kanakis GA, Nieschlag E: Klinefelter syndrome: more than hypogonadism, Metabolism 86: 135–144, 2018; Cui X, Cui Y, Shi L, Luan J, Zhou X, &amp; Han J: A basic understanding of Turner syndrome: incidence, complications, diagnosis, and treatment, Intractable Rare Dis Res 7(4): 223–228, 2018.参见Milunsky A主编：《胎儿遗传性疾病》第4版，巴尔的摩，1998年，约翰霍普金斯大学出版社，第249–285页；Kanakis GA, Nieschlag E：克氏综合征：不仅仅是性腺功能减退，Metabolism 86: 135–144, 2018；Cui X, Cui Y, Shi L, Luan J, Zhou X, & Han J：特纳综合征的基本认识：发生率、并发症、诊断和治疗，Intractable Rare Dis Res 7(4): 223–228, 2018。
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 101 I because of a failure of normal Xp/Yp recombination in the pseudoautos…
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 101 I because of a failure of normal Xp/Yp recombination in the pseudoautosomal region.疾病101的染色体和基因组基础I是由于假常染色体区正常Xp/Yp重组失败所致。
Among cases of maternal origin, most result from errors in maternal meiosis I; maternal age is increased in such cases.在母源病例中，多数是由于母体减数第一次分裂错误所致；此类病例中母亲年龄增加。
Approximately 15% of Klinefelter patients have mosaic karyotypes, most commonly 46,XY/47,XXY.大约15%的克氏综合征患者具有嵌合体核型，最常见的是46,XY/47,XXY。
As a group, such mosaic patients have variable phenotypes, and some may have normal testicular development.总体而言，这类嵌合体患者具有可变表型，部分患者可能拥有正常的睾丸发育。
Patients with Klinefelter syndrome have a several-fold increased risk for learning difficulties, especially in reading, that may require educational intervention.克氏综合征患者出现学习困难（尤其是阅读困难）的风险增加数倍，可能需要教育干预。
Language difficulties may lead to shyness, unassertiveness, apparent immaturity, and an increased risk for depression.语言困难可能导致害羞、不自信、明显不成熟以及抑郁风险增加。
In adulthood, persistent androgen deficiency may result in decreased muscle tone, a loss of libido, and decreased bone mineral density (2).成年后，持续性雄激素缺乏可能导致肌张力降低、性欲减退以及骨密度降低（2）。
The Mechanism of Sex Reversal Disorders of sex development (DSD) consists of 46,XY karyotype and 46,XX karyotype.性发育障碍（DSD）的性逆转机制包括46,XY核型和46,XX核型。
The overall incidence of DSDs associated with a 46,XY karyotype is ~0. 6 per million females.与46,XY核型相关的DSD总体发病率约为每百万女性0.6例。
Although a number of cytogenetic or single-gene defects have been demonstrated, many B A The patients are tall and thin and have relatively long legs.尽管已证实存在多种细胞遗传学或单基因缺陷，许多 B A 患者身材高瘦且腿相对较长。
They appear physically normal until puberty, when signs of hypogonadism become obvious.他们身体外观正常，直至青春期时性腺功能减退的体征变得明显。
Puberty occurs at a normal age, but the testes remain small, and secondary sexual characteristics remain underdeveloped.青春期发生在正常年龄，但睾丸仍小，且第二性征发育不全。
Note narrow shoulders and chest.注意肩部和胸部狭窄。
Gynecomastia is a feature of some Klinefelter males and is visible in the 16-year-old patient in (A) (A, From Jones KL, Jones MC, del Campo M: Smith’s recognizable patterns of human malformation, ed 7, Philadelphia, 2013, WB Saunders; B, from Grumbach MM, Hughes IA, Conte FA: Disorders of sex differentiation.男性乳房发育是部分克氏综合征男性的特征，且在（A）中的16岁患者可见（A，引自Jones KL, Jones MC, del Campo M: Smith's recognizable patterns of human malformation, 第7版, 费城, 2013, WB Saunders; B，引自Grumbach MM, Hughes IA, Conte FA: Disorders of sex differentiation.
In Larsen PR, Kronenberg HM, Melmed S, et al, eds: Williams textbook of endocrinology, ed 10, Philadelphia, 2003, WB Saunders.)见Larsen PR, Kronenberg HM, Melmed S, 等编: Williams内分泌学教科书, 第10版, 费城, 2003, WB Saunders.)
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such cases remain unexplained.
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such cases remain unexplained.此类病例仍无法解释。
Approximately 15% of patients with 46,XY complete gonadal dysgenesis (CGD) have deletions or variants in the SRY gene that interfere with the normal male pathway.大约15%的46,XY完全性性腺发育不全（CGD）患者存在SRY基因的缺失或变异，这些变异干扰了正常的男性分化通路。
However, most females with a 46,XY karyotype have an apparently normal SRY gene.然而，大多数具有46,XY核型的女性拥有表型正常的SRY基因。
The DAX1 gene in Xp 21. 3 encodes a transcription factor that plays a dosage-sensitive role in the determination of gonadal sex, implying a tightly regulated interaction between DAX1 and SRY.位于Xp21.3的DAX1基因编码一种转录因子，该因子在性腺性别决定中发挥着剂量敏感的作用，提示DAX1与SRY之间存在严格调控的相互作用。
Although production of SRY at a critical point in early development normally leads to testis formation, an excess of DAX1 resulting from duplication of the gene can apparently suppress the normal male-determining function of SRY, leading to ovarian development.尽管在早期发育的关键时间点产生SRY通常会导致睾丸形成，但DAX1基因重复导致的DAX1过量表达可明显抑制SRY的正常男性决定功能，从而导致卵巢发育。
A key master gene in gonadal development and the target of SRY signaling is the SOX9 gene on chromosome 17.性腺发育中的一个关键主控基因及SRY信号转导的靶标是位于17号染色体上的SOX9基因。
SOX9 is normally expressed early in development in the genital ridge and is required for normal testis formation.SOX9通常在发育早期于生殖嵴中表达，并且是正常睾丸形成所必需的。
Variants in one copy of the SOX9 gene, typically associated with a skeletal malformation disorder called campomelic dysplasia, lead to complete gonadal dysgenesis in ~75% of 46,XY cases ( In the absence of one copy of the SOX9 gene, testes fail to form, and the ovarian pathway is followed instead.SOX9基因单拷贝的变异，通常与一种称为“弯肢发育不良”的骨骼畸形疾病相关，导致约75%的46,XY病例出现完全性性腺发育不全（在缺少一个SOX9基因拷贝的情况下，睾丸无法形成，转而遵循卵巢发育通路）。
The phenotype of these patients suggests that the critical step for the male pathway is sufficient SOX9 expression to drive the formation of testes, normally after up-regulation by the SRY gene.这些患者的表现型提示，男性通路的关键步骤是足够的SOX9表达以驱动睾丸形成，通常在SRY基因上调后发生。
In 46,XY CGD, with either a variant in SRY or a variant in SOX9, the levels of SOX9 expression remain too low for testis differentiation, allowing ovarian differentiation to ensue.在46,XY CGD中，无论存在SRY变异还是SOX9变异，SOX9的表达水平都过低而无法促使睾丸分化，从而允许卵巢分化随后发生。
As many as 10% of patients with a range of 46,XY DSD phenotypes carry variants in the NR5A1 gene, which encodes a transcriptional regulator of a number of genes, including SOX9 and DAX1.多达10%的具有多种46,XY DSD表现型的患者携带NR5A1基因的变异，该基因编码多种基因（包括SOX9和DAX1）的转录调控因子。
These variants are associated with inadequate androgenization of external genitalia, leading to ambiguous genitalia, partial gonadal dysgenesis, and absent or rudimentary müllerian structures.这些变异与外生殖器雄激素化不足相关，导致外生殖器模糊、部分性腺发育不全以及苗勒管结构缺失或发育不全。
The second type of DSDs is a series of phenotypes known as the 46,XX testicular DSDs (previously termed XX sex reversal), which are characterized by the presence of male external genitalia in individuals with an apparently normal 46,XX karyotype.第二类DSDs是一系列被称为46,XX睾丸性DSDs（既往称为XX性反转）的表现型，其特征是核型看似正常的46,XX个体出现男性外生殖器。
The overall incidence is ~1 in 20,000.总体发病率约为1/20,000。
Most patients have a normal male appearance at birth and are not diagnosed until puberty because of small testes, gynecomastia, and infertility, despite otherwise normal-appearing male genitalia and pubic hair 6. 17 and text) Tall, but otherwise typical male appearance Hypotonia, delayed milestones; language and learning difficulties; tend to be taller than average Short stature, webbed neck, lymphedema; risk for cardiac abnormalities Cognition/ intelligence Verbal IQ reduced to lownormal range; educational difficulties Verbal IQ reduced to lownormal range; language delay; reading difficulties Normal to low-normal range (both verbal and performance IQ decreased) Typically normal, but performance IQ lower than verbal IQ Behavioral phenotype No major disorders; tendency to poor social adjustments, but normal adult relationships Subset with specific behavioral problems likely associated with lower IQ Typically, no behavioral problems; some anxiety and low self-esteem; reduced social skills Typically normal, but impaired social adjustment Sex development/ fertility Hypogonadism, azoospermia, infertility Normal Reduced fertility in some Premature ovarian failure Gonadal dysgenesis, delayed maturation, infertility Variant karyotypes See genetic. org; Skuse D, Printzlau F, Wolstencroft J: Sex chromosome aneuploidies, Handb Clin Neurol 147: 355–376, 2018..大多数患者出生时具有正常的男性外观，直至青春期因小睾丸、男性乳房发育和不育才被诊断，尽管外生殖器和阴毛外观正常（6.17及文本）；身材高大但其余男性外观典型；肌张力低下，发育里程碑延迟；语言和学习困难；身高往往高于平均水平；身材矮小，颈蹼，淋巴水肿；心脏异常风险；认知/智力：言语智商降至正常低值范围；教育困难；言语智商降至正常低值范围；语言延迟；阅读困难；正常至正常低值范围（言语智商和操作智商均下降）；通常正常，但操作智商低于言语智商；行为表型：无重大障碍；社交适应不良倾向，但成年后人际关系正常；部分有特定行为问题，可能智商较低；通常无行为问题；部分焦虑和自卑；社交技能降低；通常正常，但社交适应受损；性发育/生育：性腺功能减退，无精子症，不育；正常；部分生育力降低；卵巢早衰；性腺发育不全，成熟延迟，不育；变异核型：参见genetic.org；Skuse D, Printzlau F, Wolstencroft J: Sex chromosome aneuploidies, Handb Clin Neurol 147: 355–376, 2018..
DISORDERS OF GONADAL DEVELOPMENT Gonadal dysgenesis refers to a progressive loss of germ cells, typically leading to underdeveloped and dysfunctional (streak) gonads, with consequent failure to develop mature secondary sex characteristics.性腺发育障碍：性腺发育不全是指生殖细胞进行性丢失，通常导致性腺发育不良和功能不全（条索性腺），进而无法发育出成熟的第二性征。
Complete gonadal dysgenesis (CGD) – as in the case of XX males (now formally designated 46,XX testicular CGD) or XY females (now formally designated 46,XY CGD) – is characterized by normal-appearing external genitalia of the opposite chromosomal sex.完全性性腺发育不全（CGD）——如XX男性（现正式命名为46,XX睾丸性CGD）或XY女性（现正式命名为46,XY CGD）——其特征是出现与染色体性别相反且外观正常的外生殖器。
Cases with ambiguous external genitalia are said to have partial gonadal dysgenesis.外生殖器模糊的病例被认为患有部分性性腺发育不全。
Various types of gonadal dysgenesis, their clinical phenotypes, and genetic causes are summarized in各类性腺发育不全、其临床表型及遗传原因总结于
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 103 3 SRY variant Female, XY gonadal dysgenesis DAX1 (NR0B1) Xp 21. 3 DAX1 …
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 103 3 SRY variant Female, XY gonadal dysgenesis DAX1 (NR0B1) Xp 21. 3 DAX1 gene duplication Female, XY gonadal dysgenesis SOX9 17q24 SOX9 variant Female, XY gonadal dysgenesis, with campomelic dysplasia NR5A1 9q33 NRSA1 variant Ambiguous genitalia, XY partial gonadal dysgenesis WNT4 1p35 WNT4 gene duplication Ambiguous genitalia, cryptorchidism AR Xq 12 AR variant Female, complete or partial androgen insensitivity syndrome 46,XX Karyotype SRY Yp 11. 3 SRY gene translocated to X Male, XX (ovo)testicular DSD SOX3 Xq 27. 1 SOX3 gene duplication Male, XX testicular DSD SOX9 17q24 SOX9 gene duplication Male, XX testicular DSD CYP21A2 6p21. 3 CYP21A2 variant Ambiguous genitalia, virilization, micropenis DSD, Disorder of sex development.疾病的染色体和基因组基础 103 3 SRY变异 女性，XY性腺发育不全 DAX1（NR0B1）Xp21.3 DAX1基因重复 女性，XY性腺发育不全 SOX9 17q24 SOX9变异 女性，XY性腺发育不全伴弯肢发育不良 NR5A1 9q33 NR5A1变异 外生殖器模糊，XY部分性腺发育不全 WNT4 1p35 WNT4基因重复 外生殖器模糊，隐睾 AR Xq12 AR变异 女性，完全性或部分性雄激素不敏感综合征 46,XX核型 SRY Yp11.3 SRY基因易位至X 男性，XX（卵）睾丸性DSD SOX3 Xq27.1 SOX3基因重复 男性，XX睾丸性DSD SOX9 17q24 SOX9基因重复 男性，XX睾丸性DSD CYP21A2 6p21.3 CYP21A2变异 外生殖器模糊，男性化，小阴茎 DSD，性发育异常。
Updated from Achermann JC, Hughes IA: Disorders of sex development.更新自 Achermann JC, Hughes IA: 性发育异常。
In Melmed S, Polonsky KS, Larsen PR, et al, eds: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, WB Saunders, pp 886–934; and Witchel SF: Disorders of sex development, Best Pract Res Clin Obstet Gynaecol 48: 90–102, 2018.见 Melmed S, Polonsky KS, Larsen PR 等编：《威廉姆斯内分泌学教科书》，第12版，费城，2011年，WB Saunders出版，第886–934页；以及 Witchel SF: 性发育异常，Best Pract Res Clin Obstet Gynaecol 48: 90–102, 2018。
Summarized from Achermann JC, Hughes IA: Disorders of sex development.总结自 Achermann JC, Hughes IA: 性发育异常。
In Melmed S, Polonsky KS, Larsen PR, et al, eds: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, WB Saunders, pp 886–934; Pagon RA, Adam MP, Bird TD, et al, eds: Gene Reviews [Internet].见 Melmed S, Polonsky KS, Larsen PR 等编：《威廉姆斯内分泌学教科书》，第12版，费城，2011年，WB Saunders出版，第886–934页；Pagon RA, Adam MP, Bird TD 等编：《基因评论》[互联网]。
Seattle, 1993–2013, University of Washington, Seattle, and Witchel SF: Disorders of sex development, Best Pract Res Clin Obstet Gynaecol 48:90–102, 2018.西雅图，1993–2013，华盛顿大学西雅图分校，以及 Witchel SF: 性发育异常，Best Pract Res Clin Obstet Gynaecol 48:90–102, 2018。
( As described previously in the section on the Y chromosome, most of these individuals are found to have a copy of a normal SRY gene translocated to an X chromosome as a result of aberrant recombination.（如前文Y染色体部分所述，大多数此类个体因异常重组而携带一个正常SRY基因拷贝易位至X染色体。
Those 46,XX males who lack an SRY gene, however, are a clinically more heterogeneous group.然而，那些缺乏SRY基因的46,XX男性在临床上是一组更具异质性的群体。
Approxi­ mately 15% to 20% of such patients are identifiable at birth because of ambiguous genitalia, including penoscrotal hypospadias and cryptorchidism (undescended testes); there are no identifiable müllerian structures, and their gender identity is male.此类患者中约15%至20%在出生时因外生殖器模糊（包括阴茎阴囊型尿道下裂和隐睾（未降睾丸））而被识别；无可识别的苗勒管结构，其性别认同为男性。
A somewhat smaller percentage of patients, however, have both testicular and ovarian tissue, either as an ovotestis or as a separate ovary and testis, a condition known as 46,XX ovotesticular DSD (formerly called true hermaphroditism).然而，比例略小的患者同时具有睾丸和卵巢组织，表现为卵睾或分离的卵巢和睾丸，即46,XX卵睾丸性DSD（旧称真两性畸形）。
Individuals with either testicular DSD or ovotesticular DSD who lack a translocated SRY gene have been the subject of an intense investigation to identify the responsible genetic causes.缺乏易位SRY基因的睾丸性DSD或卵睾丸性DSD个体一直是深入研究以确定其遗传病因的对象。
Duplications of at least two genes have been described, suggesting that increased levels of transcriptional regulators can overcome the absence of SRY and initiate the testis-specific pathway (see Both gene duplications and regulatory variants can increase the level of SOX9 expression to bypass the requirement for SRY.至少有两大基因的重复已被描述，提示转录调控因子水平升高可克服SRY缺失并启动睾丸特异性通路（见 基因重复和调控变异均可提高SOX9表达水平，从而绕过对SRY的需求。
Similarly, duplications of the X-linked SOX3 gene, which is very closely related in sequence to the SRY gene, can stimulate increased SOX9 expression, replacing the usual need for SRY (3).类似地，X连锁SOX3基因（其序列与SRY基因高度相似）的重复可刺激SOX9表达升高，替代通常所需的SRY（3）。
Virilization of 46,XX Infants: Congenital Adrenal Hyperplasia These patients include those who have 46,XX karyotypes with a normal uterus and ovaries but with46,XX婴儿的男性化：先天性肾上腺皮质增生症 这些患者包括具有正常子宫和卵巢但……的46,XX核型患者。
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See text for discussion.
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See text for discussion.参见正文讨论。
(From Moore KL, Persaud TVN: The developing human: clinically oriented embryology, ed 5, Philadelphia, 1993, WB Saunders.) 3 OVARIAN DEVELOPMENT AND MAINTENANCE Ovarian maintenance typically lasts for up to 5 decades in normal females.(摘自Moore KL, Persaud TVN: The developing human: clinically oriented embryology, 第5版, 费城, 1993, WB Saunders.) 3 卵巢发育与维持 正常女性卵巢维持通常可持续长达50年。
Loss of normal ovarian function before the age of 40, as seen in ~1% of women, is considered premature ovarian failure (or premature ovarian insufficiency).在40岁之前丧失正常卵巢功能（见于约1%的女性）被认为是卵巢早衰（或早发性卵巢功能不全）。
It has long been thought that two X chromosomes are necessary for ovarian maintenance because 45,X females, despite normal initiation of ovarian development in utero, are characterized by germ cell loss, oocyte degeneration, and ovarian dysgenesis.长期以来人们认为两个X染色体对于卵巢维持是必需的，因为45,X女性尽管在子宫内卵巢发育起始正常，但特征为生殖细胞丢失、卵母细胞退化和卵巢发育不全。
Further, patients with 47,XXX or with cytogenetic abnormalities involving Xq, as well as carriers of fragile X syndrome (Case 17), frequently show premature ovarian failure.此外，47,XXX患者或涉及Xq的细胞遗传学异常患者，以及脆性X综合征携带者（病例17），常出现卵巢早衰。
Because many nonoverlapping deletions on Xq show the same effect, this finding may reflect a need for two structurally normal X chromosomes in oogenesis or simply a requirement for multiple X-linked genes.由于Xq上许多非重叠缺失显示出相同效应，这一发现可能反映了卵子发生需要两个结构正常的X染色体，或者仅仅需要多个X连锁基因。
Nearly a dozen specific genes, such as desert hedgehog gene (DHH), have been implicated in ­familial cases of premature ovarian failure and in various forms of 46,XX gonadal dysgenesis. ambiguous or male external genitalia due to excessive virilization.近十种特定基因，如沙漠刺猬基因（DHH），已被涉及家族性卵巢早衰病例及多种形式的46,XX性腺发育不全，表现为因过度男性化导致的外生殖器模糊或男性化。
The majority of such patients have congenital adrenal hyperplasia (CAH), an inherited disorder arising from specific defects in enzymes of the adrenal cortex required for cortisol biosynthesis and resulting in excess androgen production.这类患者大多数患有先天性肾上腺皮质增生症（CAH），这是一种遗传性疾病，源于肾上腺皮质中参与皮质醇生物合成所需的特定酶缺陷，导致雄激素过度产生。
In addition to being a frequent cause of female virilization, CAH accounts for approximately half of all cases presenting with ambiguous external genitalia.除了是女性男性化的常见原因外，CAH约占所有表现为外生殖器模糊病例的一半。
Ovarian development is normal, but excessive production of androgens causes masculinization of the external genitalia, with clitoral enlargement and labial fusion to form a scrotum-like structure .卵巢发育正常，但雄激素过度产生导致外生殖器男性化，表现为阴蒂增大和阴唇融合形成类似阴囊的结构。
Androgen Insensitivity Syndrome There are several forms of androgen insensitivity that result in incomplete masculinization of 46,XY individuals.雄激素不敏感综合征 有几种形式的雄激素不敏感导致46,XY个体男性化不完全。
Here we illustrate the essential principles by considering the X-linked syndrome known as androgen insensitivity syndrome.这里我们通过考虑称为雄激素不敏感综合征的X连锁综合征来阐述基本原理。
As the original name indicates, testes are present either within the abdomen or in the inguinal canal, where they are sometimes mistaken for hernias in infants who otherwise appear to be normal females.如其原名所示，睾丸位于腹腔内或腹股沟管内，在婴儿中有时被误认为疝气，而这些婴儿在其他方面表现为正常女性。
Although the testes in these patients secrete androgen normally, end-organ unresponsiveness to androgens results from an absence of androgen receptors in the appropriate target cells.尽管这些患者的睾丸正常分泌雄激素，但由于相应靶细胞中缺乏雄激素受体，导致终末器官对雄激素无反应。
The receptor protein, specified by the normal allele at the X-linked androgen receptor (AR) locus, has the role of forming a complex with testosterone and dihydrotestosterone.由X连锁雄激素受体（AR）基因座的正常等位基因编码的受体蛋白，其作用是与睾酮和双氢睾酮形成复合物。
If the complex fails to form, the hormone fails to stimulate the transcription of target genes required for differentiation in the male direction.如果复合物未能形成，激素就无法刺激向男性方向分化所需靶基因的转录。
The molecular defect has been determined in many hundreds of cases and ranges from a complete deletion of the AR gene to point variants in the androgen-binding or DNA-binding domains of the androgen receptor protein.数百个病例中已确定了分子缺陷，范围从AR基因的完全缺失到雄激素受体蛋白的雄激素结合域或DNA结合域的点突变。
Affected individuals are chromosomal males (karyotype 46,XY) who have apparently normal female external genitalia but have a blind vagina (the female reproductive canal that ends in a sac and does not connect to internal genitalia) and no uterus or fallopian tubes.受累个体为染色体男性（核型46,XY），具有明显正常的女性外生殖器，但有一个盲端阴道（女性生殖管道，末端为盲囊，不与内生殖器相连），且无子宫或输卵管。
The incidence of androgen insensitivity is ~1 in 10,000 to 20,000 live births, and both complete and partial forms are known, depending on the severity of the genetic defect.雄激素不敏感的发生率约为每10,000至20,000例活产中1例，已知有完全型和部分型，取决于遗传缺陷的严重程度。
In the complete form , axillary and pubic hair are sparse or absent, and breast development occurs at the appropriate age but without menses; primary amenorrhoea is frequently the presenting clinical finding that leads to a diagnosis.在完全型中，腋毛和阴毛稀疏或缺如，乳房在适龄发育但无月经；原发性闭经常常是导致诊断的临床表现。
TECHNOLOGIES USED IN DIAGNOSTIC TESTING Microarrays, short-read (SR) whole exome sequencing, and whole genome sequencing are the most widely utilized cost-effective diagnostic methods (see Chapter 5).诊断检测中使用的技术 微阵列、短读长全外显子组测序和全基因组测序是最广泛应用的经济有效的诊断方法（见第5章）。
But to find novel variations, SV calling methods from de novo assembled haplotype-resolved genomes using high-coverage sequencing should be utilized.但为了发现新变异，应使用基于高深度测序从头组装单倍型分辨基因组的SV检测方法。
Accurate detection, genotyping, and annotation of SVs are only a few of the difficulties that must be overcome for accurate SV detection in clinical settings.SV的准确检测、基因分型和注释只是临床环境中准确检测SV必须克服的少数困难之一。
Determining the frequency of the variants in the population is critical to confirm that they occur at a sufficiently low frequency to call pathogenic variants.确定变异在人群中的频率对于确认其发生频率足够低以判定为致病性变异至关重要。
While it is possible to evaluate虽然可以评估。
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 105 the frequency of SNVs using reference datasets like gnom AD, this is si…
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 105 the frequency of SNVs using reference datasets like gnom AD, this is significantly more challenging for SVs, even though several recent population-scale studies provide much-needed SV assessment and annotation.利用gnomAD等参考数据集估算SNV频率，而对于SV来说这一过程要困难得多，尽管近期几项人群规模研究提供了亟需的SV评估与注释。
Despite the fact that there are only a few potential SNVs at each site, the number of potential SVs that could affect each site is significantly greater because of the differences in their size and type.尽管每个位点仅存在少数潜在SNV，但由于SV在大小和类型上的差异，可能影响每个位点的潜在SV数量要显著更多。
The ability to compare SVs to one another is further complicated by this.这使得SV之间相互比较的能力进一步复杂化。
Because of this, it’s essential to use advanced methods like long read (LR) sequencing and genomic data from many diverse populations.因此，有必要采用先进方法，如长读长测序以及来自多个不同人群的基因组数据。
The significance of selecting the proper SV calling algorithm is another facet of SVs.选择合适的SV检测算法的重要性是SV的另一个方面。
Using simulated and actual whole genome sequencing datasets, Kosugi and colleagues assessed the performance of 69 existing SR sequencing SV detection algorithms.Kosugi等利用模拟和真实的全基因组测序数据集，评估了69种现有短读长测序SV检测算法的性能。
They concluded that the following algorithms perform better in the deletion or duplication categories: GRIDSS, Lumpy, SVseq 2, Soft SV, Manta, and Wham.他们得出结论，以下算法在缺失或重复类别中表现更优：GRIDSS、Lumpy、SVseq2、SoftSV、Manta和Wham。
Numerous SV algorithms are frequently employed to increase the accuracy of SV calling and overlaps across techniques for all types and size ranges of SV are assessed.多种SV算法常被用于提高SV检测的准确性，并对所有类型和大小范围的SV在不同技术间的重叠情况进行评估。
These findings imply that careful algorithm selection is necessary for each type and size range of SVs to accurately call SVs.这些发现表明，为了准确地检测SV，需要对每种类型和大小范围的SV仔细选择算法。
Recent research has demonstrated that SV calling based on LR sequencing data should also consider a similar strategy.近期研究表明，基于长读长测序数据的SV检测也应考虑类似的策略。
An alternate technology is necessary due to the shortcomings of the present cytogenetic techniques, such as chromosomal microarray and SR-based sequencing.由于现有细胞遗传学技术（如染色体微阵列和基于短读长的测序）的缺陷，有必要采用替代技术。
Sequencing techniques are quite good at finding SVs, but they struggle to resolve complex regions of the genome precisely, necessitating the use of an orthogonal technique to detect and validate the SVs.测序技术非常善于发现SV，但难以精确解析基因组的复杂区域，因此需要使用正交技术来检测和验证SV。
Optical mapping is another technique that has been demonstrated to elucidate complex regions in SDs and detect SVs in these regions, some of which are associated with deletion and duplication syndromes.光学图谱是另一种技术，已被证明可以阐明分段重复中的复杂区域，并检测这些区域中的SV，其中一些SV与缺失和重复综合征相关。
Compared to LR-based sequencing approaches, optical mapping is less expensive and has the capacity to resolve complex SVs, which shows its potential as a diagnostic tool in clinical investigations.与基于长读长的测序方法相比，光学图谱成本较低，且能够解析复杂SV，这显示了其在临床研究中作为诊断工具的潜力。
Diagnostics depend on the accurate detection of all types of genetic disorders by optical mapping, including deletion and duplication syndromes, aneuploidies, sex chromosomal abnormalities, and disorders involving repeat expansion/contraction.诊断依赖于通过光学图谱准确检测所有类型的遗传疾病，包括缺失和重复综合征、非整倍体、性染色体异常以及涉及重复扩增/收缩的疾病。
DATABASES OF GENOMIC VARIANTS Name URL Description DECIPHER deciphergenomics. org/ “The DECIPHER database contains data from 40,078 patients who have given consent for broad data-sharing” NCBIClin Var nih. gov/clinvar/ “Clin Var is a public archive with free access to reports on the relationships between human variations and phenotypes, with supporting evidence.” OMIM “Online Mendelian Inheritance in Man, An Online Catalog of Human Genes and Genetic Disorders” DGV app/home “Database of genomic variants containing variants identified in individuals without any known diseases or disorders” gnom AD broadinstitute. org/ Genome Aggregation Database Note female body contours, breast development, absence of axillary hair, and sparse pubic hair.基因组变异数据库的名称、网址和描述如下：DECIPHER deciphergenomics.org/ “DECIPHER数据库包含来自40,078名同意广泛数据共享的患者的数据”；NCBIClinVar nih.gov/clinvar/ “ClinVar是一个公共档案库，免费提供关于人类变异与表型之间关系的报告及其支持证据”；OMIM “在线人类孟德尔遗传，人类基因和遗传疾病在线目录”；DGV app/home “基因组变异数据库，包含来自无已知疾病或障碍个体的变异”；gnomAD broadinstitute.org/ 基因组聚合数据库；注意女性身体轮廓、乳房发育、腋毛缺失和阴毛稀疏。
(Courtesy L.（致谢L.
Pinsky, Mc Gill University, Montreal, Canada.)Pinsky，加拿大蒙特利尔麦吉尔大学。）
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GENERAL REFERENCES Achermann JC, Hughes IA: Disorders of sex development.
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GENERAL REFERENCES Achermann JC, Hughes IA: Disorders of sex development.一般参考文献 Achermann JC, Hughes IA: 性发育异常。
In Melmed S, Polonsky KS, Larsen PR, editors: Williams textbook of endocrinology ed 12, Philadelphia, 2011, WB Saunders, pp 886–934.见 Melmed S, Polonsky KS, Larsen PR 编:《威廉姆斯内分泌学教科书》第12版, 费城, 2011年, WB Saunders, 第886–934页。
Gardner RJM, Sutherland GR, Shaffer LG: Chromosome abnormalities and genetic counseling, ed 4, Oxford, England, 2012, Oxford University Press.Gardner RJM, Sutherland GR, Shaffer LG:《染色体异常与遗传咨询》第4版, 英国牛津, 2012年, 牛津大学出版社。
Moore KL, Persaud TVN, Torchia MG: The developing human: ­clinically oriented embryology, ed 9, Philadelphia, 2013, WB Saunders.Moore KL, Persaud TVN, Torchia MG:《人体发育:临床导向胚胎学》第9版, 费城, 2013年, WB Saunders。
REFERENCES FOR SPECIFIC TOPICS 100,000 Genomes Project Pilot Investigators, Smedley D, Smith KR, et al: 100,000 genomes pilot on rare-disease diagnosis in health care – preliminary report, NEJM 385:1868–1880, 2021.特定主题参考文献 100,000 Genomes Project Pilot Investigators, Smedley D, Smith KR, 等: 10万基因组试点研究在医疗保健中用于罕见病诊断——初步报告, NEJM 385:1868–1880, 2021。
Allen EG, Freeman SB, Druschel C, et al: Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects, Human Gen 125:41–52, 2009.Allen EG, Freeman SB, Druschel C, 等: 根据染色体不分离起源评估的母亲年龄与21三体风险:来自亚特兰大和国家唐氏综合征项目的报告, Human Gen 125:41–52, 2009。
Bartolomei MS, Ferguson-Smith AC: Mammalian genomic imprinting, Cold Spring Harb Perspect Biol 3:a 002592, 2011.Bartolomei MS, Ferguson-Smith AC: 哺乳动物基因组印记, Cold Spring Harb Perspect Biol 3:a002592, 2011。
Baxter R, Vilain R: Translational genetics for diagnosis of human disorders of sex development, Annu Rev Genomics Hum Genet 14:371–392, 2013.Baxter R, Vilain R: 用于人类性发育异常诊断的转化遗传学, Annu Rev Genomics Hum Genet 14:371–392, 2013。
Berglund A, Johannsen TH, Stochholm K, et al: Incidence, prevalence, diagnostic delay, and clinical presentation of female 46, XY disorders of sex development, J Clin Endocrinol Metab 101:4532– 4540, 2016.Berglund A, Johannsen TH, Stochholm K, 等: 女性46,XY性发育异常的发病率、患病率、诊断延迟及临床表现, J Clin Endocrinol Metab 101:4532–4540, 2016。
Carvalho CM, Lupski JR: Mechanisms underlying structural variant formation in genomic disorders, Nat Rev Genet 17:224–238, 2016.Carvalho CM, Lupski JR: 基因组疾病中结构变异形成的机制, Nat Rev Genet 17:224–238, 2016。
Cassidy SB, Schwartz S, Miller JL, et al: Prader-Willi syndrome, Genet Med 14:10–26, 2012.Cassidy SB, Schwartz S, Miller JL, 等: 普拉德-威利综合征, Genet Med 14:10–26, 2012。
Chaisson MJ, Sanders AD, Zhao X, et al: Multi-platform discovery of haplotype-resolved structural variation in human genomes, Nat Comm 10:1–16, 2019.Chaisson MJ, Sanders AD, Zhao X, 等: 人类基因组中单倍型解析结构变异的多平台发现, Nat Comm 10:1–16, 2019。
Cooper GM, Coe BP, Girirajan S, et al: A copy number variation morbidity map of developmental delay, Nat Genet 43:838–846, 2011.Cooper GM, Coe BP, Girirajan S, 等: 发育迟缓的拷贝数变异发病率图谱, Nat Genet 43:838–846, 2011。
Cui X, Cui Y, Shi L, Luan J, Zhou X, Han J: A basic understanding of Turner syndrome: incidence, complications, diagnosis, and treatment, Intractable Rare Dis Res 7(4):223–228, 2018. de Ligt J, Willemsen H, van Bon BWM, et al: Diagnostic exome sequencing in persons with severe intellectual disability, NEJM 367:1921–1929, 2012.Cui X, Cui Y, Shi L, Luan J, Zhou X, Han J: 特纳综合征的基本认识:发病率、并发症、诊断和治疗, Intractable Rare Dis Res 7(4):223–228, 2018。de Ligt J, Willemsen H, van Bon BWM, 等: 重度智力障碍患者的外显子组诊断测序, NEJM 367:1921–1929, 2012。
Dittwald P, Gambin T, Szafranski P, et al: NAHR-mediated copynumber variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits, Genome Res 23(9): 1395–1409, 2013.Dittwald P, Gambin T, Szafranski P, 等: 临床人群中NAHR介导的拷贝数变异:对基因组疾病和孟德尔化特征的机制性见解, Genome Res 23(9):1395–1409, 2013。
Ellison JW, Rosenfeld JA, Shaffer LG: Genetic basis of intellectual disability, Ann Rev Med 64:441–450, 2013.Ellison JW, Rosenfeld JA, Shaffer LG: 智力障碍的遗传基础, Ann Rev Med 64:441–450, 2013。
Fang H, Disteche CM, Berletch JB: X inactivation and escape: epigenetic and structural features, Front Cell Dev Biol:219, 2019.Fang H, Disteche CM, Berletch JB: X失活与逃逸:表观遗传和结构特征, Front Cell Dev Biol:219, 2019。
Gajecka M, Mac Kay KL, Shaffer LG: Monosomy 1p36 deletion syndrome, Am J Med Genet Part C Semin Med Genet 145C:346–356, 2007.Gajecka M, Mac Kay KL, Shaffer LG: 1p36单体性缺失综合征, Am J Med Genet Part C Semin Med Genet 145C:346–356, 2007。
Gebhardt GS, Devriendt K, Thoelen R, et al: No evidence for a parental inversion polymorphism predisposing to rearrangements at 22q11. 2 in the Di George/velocardiofacial syndrome, Eur J Human Gen 11:109–111, 2003.Gebhardt GS, Devriendt K, Thoelen R, 等: 无证据表明存在易感22q11.2重排的亲本倒位多态性在迪乔治/腭心面综合征中, Eur J Human Gen 11:109–111, 2003。
Higgins AW, Alkuraya FS, Bosco AF, et al: Characterization of apparently balanced chromosomal rearrangements from the Developmental Genome Anatomy Project, Am J Hum Genet 82:712–722, 2008.Higgins AW, Alkuraya FS, Bosco AF, 等: 来自发育基因组解剖项目的表观平衡染色体重排的特征分析, Am J Hum Genet 82:712–722, 2008。
Hughes IA, Davies JD, Bunch TI, et al: Androgen insensitivity syndrome, Lancet 380:1419–1428, 2012.Hughes IA, Davies JD, Bunch TI, 等: 雄激素不敏感综合征, Lancet 380:1419–1428, 2012。
Hughes IA, Houk C, Ahmed SF, et al: Consensus statement on ­management of intersex disorders, Arch Dis Child 91:554–563, 2006.Hughes IA, Houk C, Ahmed SF, 等: 关于两性畸形障碍处理的共识声明, Arch Dis Child 91:554–563, 2006。
Huguet G, Ey E, Bourgeron T: The genetic landscapes of autism spectrum disorders, Ann Rev Genomics Hum Genet 14:191–213, 2013.Huguet G, Ey E, Bourgeron T: 自闭症谱系障碍的遗传景观, Ann Rev Genomics Hum Genet 14:191–213, 2013。
Jiang Y, Yuen RKC, Jin X, et al: Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing, Am J Hum Genet 93:1–15, 2013.Jiang Y, Yuen RKC, Jin X, 等: 通过全基因组测序检测自闭症谱系障碍中临床相关的遗传变异, Am J Hum Genet 93:1–15, 2013。
Kaminsky EB, Kaul V, Paschall J, et al: An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities, Genet Med 13: 777–784, 2011.Kaminsky EB, Kaul V, Paschall J, 等: 建立智力及发育障碍中拷贝数变异功能与临床意义的循证方法, Genet Med 13:777–784, 2011。
Kanakis GA, Nieschlag E: Klinefelter syndrome: more than hypogonadism, Metabolism 86:135–144, 2018.Kanakis GA, Nieschlag E: 克兰费尔特综合征:不止是性腺功能减退, Metabolism 86:135–144, 2018。
Kazazian HH Jr, Moran JV: Mobile DNA in health and disease, NEJM 377:361–370, 2017.Kazazian HH Jr, Moran JV: 健康与疾病中的移动DNA, NEJM 377:361–370, 2017。
Kessler MD, Yerges-Armstrong L, Taub MA, et al: Challenges and disparities in the application of personalized genomic medicine to populations with African ancestry, Nature communications 7(1):1–8, 2016.Kessler MD, Yerges-Armstrong L, Taub MA, 等: 个体化基因组医学在非洲血统人群应用中的挑战与差异, Nature communications 7(1):1–8, 2016。
Korbel JO, Tirosh-Wagner T, Urban AE, et al: The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies, Proc Natl Acad Sci USA 106:12031–12036, 2009.Korbel JO, Tirosh-Wagner T, Urban AE, 等: 通过人类节段性三体的高分辨率分析揭示的唐氏综合征表型遗传架构, Proc Natl Acad Sci USA 106:12031–12036, 2009。
Kosugi S, Momozawa Y, Liu X, et al: Comprehensive evaluation of structural variation detection algorithms for whole genome sequencing, Genome Biol 20:1–18, 2019.Kosugi S, Momozawa Y, Liu X, 等: 全基因组测序结构变异检测算法的综合评估, Genome Biol 20:1–18, 2019。
Leggett V, Jacobs P, Nation K, et al: Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review, Dev Med Child Neurol 52:119–129, 2010.Leggett V, Jacobs P, Nation K, 等: 性染色体三体个体(XXX、XYY或XXY)的神经认知结局:系统综述, Dev Med Child Neurol 52:119–129, 2010。
Mabb AM, Judson MC, Zylka MJ, et al: Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes, Trends Neurosci 34:293–303, 2011.Mabb AM, Judson MC, Zylka MJ, 等: 安吉尔曼综合征:基因组印记与神经发育表型的见解, Trends Neurosci 34:293–303, 2011。
Malhotra D, Sebat J: CNVs: harbingers of a rare variant revolution in psychiatric genetics, Cell 148:1223–1241, 2012.Malhotra D, Sebat J: CNV:罕见变异革命在精神科遗传学中的前兆, Cell 148:1223–1241, 2012。
Mc Donald-Mc Ginn DM, Sullivan KE, Marino B, et al: 22q11. 2 deletion syndrome, Nat Rev Dis Prim 1:1–19, 2015.Mc Donald-Mc Ginn DM, Sullivan KE, Marino B, 等: 22q11.2缺失综合征, Nat Rev Dis Prim 1:1–19, 2015。
Miga KH, Koren S, Rhie A, et al: Telomere-to-telomere assembly of a complete human X chromosome, Nature 585:79–84, 2020.Miga KH, Koren S, Rhie A, 等: 完整人类X染色体的端粒到端粒组装, Nature 585:79–84, 2020。
Moreno-De-Luca A, Myers SM, Challman TD, et al: Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence, Lancet Neurol 12:406–414, 2013.Moreno-De-Luca A, Myers SM, Challman TD, 等: 发育性脑功能障碍:基于新遗传证据的旧概念复兴与扩展, Lancet Neurol 12:406–414, 2013。
Morris JK, Alberman E, Mutton D, et al: Cytogenetic and epidemiological findings in Down syndrome: England and Wales 1989– 2009, Am J Med Genet A 158A:1151–1157, 2012.Morris JK, Alberman E, Mutton D, 等: 唐氏综合征的细胞遗传学与流行病学发现:英格兰和威尔士1989–2009, Am J Med Genet A 158A:1151–1157, 2012。
Mulle JG: The 3q29 deletion confers &gt;40-fold increase in risk for schizophrenia, Mol Psych 20:1028–1029, 2015.Mulle JG: 3q29缺失使精神分裂症风险增加>40倍, Mol Psych 20:1028–1029, 2015。
Najmabadi H, Hu H, Garshasbi M, et al: Deep sequencing reveals 50 novel genes for recessive cognitive disorders, Nature 478:57–63, 2011.Najmabadi H, Hu H, Garshasbi M, 等: 深度测序揭示50个新的隐性认知障碍基因, Nature 478:57–63, 2011。
Rodriguez-Martin B, Alvarez EG, Baez-Ortega A, et al: Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition, Nat Genet 52:306–319, 2020.Rodriguez-Martin B, Alvarez EG, Baez-Ortega A, 等: 全基因组泛癌分析识别由LINE-1逆转录转座驱动的重排驱动因子, Nat Genet 52:306–319, 2020。
Sanders SJ, Ercan-Sencicek AG, Hus V, et al: Multiple recurrent de novo CNVs, including duplications of the 7q11..Sanders SJ, Ercan-Sencicek AG, Hus V, 等: 多个复发性新生CNV, 包括7q11..
Williams syndrome region, are strongly associated with autism, Neuron 70: 863–885, 2011.威廉姆斯综合征区域, 与自闭症强烈相关, Neuron 70:863–885, 2011。
Silber SJ: The Y chromosome in the era of intracytoplasmic sperm injection, Fertil Steril 95:2439–2448, 2011.Silber SJ: 卵胞浆内单精子注射时代的Y染色体, Fertil Steril 95:2439–2448, 2011。
Talkowski ME, Maussion G, Crapper L, et al: Disruption of a large intergenic noncoding RNA in subjects with neurodevelopmental disabilities, Am J Hum Genet 91:1128–1134, 2012.Talkowski ME, Maussion G, Crapper L, 等: 神经发育障碍患者中一个大基因间非编码RNA的破坏, Am J Hum Genet 91:1128–1134, 2012。
Talkowski ME, Rosenfeld JA, Blumenthal I, et al: Sequencing ­chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries, Cell 149:525–537, 2012.Talkowski ME, Rosenfeld JA, Blumenthal I, 等: 染色体异常测序揭示跨诊断边界风险的神经发育位点, Cell 149:525–537, 2012。
Umehara F, Tate G, Itoh K, et al: A novel variant of desert hedgehog in a patient with 46, XY partial gonadal dysgenesis accompanied by minifascicular neuropathy, Am J Hum Genet 67:1302–1305, 2000.Umehara F, Tate G, Itoh K, 等: 一例46,XY部分性腺发育不全伴小神经束性神经病变患者中沙漠刺猬基因的新变异, Am J Hum Genet 67:1302–1305, 2000。
Watson CT, Tomas MB, Sharp AJ, et al: The genetics of microdeletion and microduplication syndromes: an update, Ann Rev Gen Hum Genet 15:215–244, 2014.Watson CT, Tomas MB, Sharp AJ, 等: 微缺失和微重复综合征的遗传学:最新进展, Ann Rev Gen Hum Genet 15:215–244, 2014。
Weischenfeldt J, Symmns O, Spitz F, et al: Phenotypic impact of genomic structural variation: insights from and for human disease, Nat Rev Genet 14:125–138, 2013.Weischenfeldt J, Symmns O, Spitz F, 等: 基因组结构变异的表型影响:来自人类疾病及其对疾病认识的见解, Nat Rev Genet 14:125–138, 2013。
Yilmaz F, Gurusamy U, Mosley T, et al: Multi-modal investigation of the schizophrenia-associated 3q29 genomic interval reveals global genetic diversity with unique haplotypes and segments that increase the risk for non-allelic homologous recombination, med Rxiv, 2021.Yilmaz F, Gurusamy U, Mosley T, 等: 精神分裂症相关3q29基因组区间的多模态研究揭示全球遗传多样性, 具有增加非等位同源重组风险的单倍型和片段, med Rxiv, 2021。
Zarrei M, Mac Donald JR, Merico D, Scherer SW.Zarrei M, Mac Donald JR, Merico D, Scherer SW.
A copy number variation map of the human genome.人类基因组拷贝数变异图谱。
Nat Rev Genet.Nat Rev Genet.
Mar; 16(3):172–83. doi:10. 1038/nrg 3871.3月; 16(3):172–83. doi:10.1038/nrg3871。
Epub 2015 Feb 3.在线发表2015年2月3日。
PMID: 25645873.PMID: 25645873。
Zufferey F, Sherr EH, Beckmann ND, et al: A 600 kb deletion syndrome at 16p11. 2 leads to energy imbalance and neuropsychiatric disorders, J Med Genet 49:660–668, 2013.Zufferey F, Sherr EH, Beckmann ND, 等: 16p11.2处一个600 kb缺失综合征导致能量失衡和神经精神障碍, J Med Genet 49:660–668, 2013。
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THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 107 1.
Ch6 — Segment 29
THE CHROMOSOMAL AND GENOMIC BASIS OF DISEASE 107 1.疾病的染色体和基因组基础 107 1.
In a woman with a 47,XXX karyotype, what types of gametes would theoretically be formed and in what proportions?在一名具有47,XXX核型的女性中，理论上会形成哪些类型的配子，以及各自的比例是多少？
What are the theoretical karyotypes and phenotypes of her progeny?她后代的假想核型和表型是什么？
What are the actual karyotypes and phenotypes of her progeny?她后代的实际核型和表型是什么？
Individuals carrying a copy of the inv(9) described in the text are clinically normal.携带文中描述的inv(9)的个体在临床上表现正常。
Provide two possible explanations.提供两种可能的解释。
The birth incidence rates of 47,XXY and 47,XYY males are approximately equal.47,XXY和47,XYY男性的出生发生率大致相等。
Is this what you would expect on the basis of the possible origins of the two abnormal karyotypes?根据这两种异常核型可能的起源，这是否符合你的预期？
How can a person with an XX karyotype differentiate as a phenotypically normal male?一个具有XX核型的人如何分化成表型正常的男性？
A small centric ring X chromosome that lacks the X inactivation center is observed in a patient with short stature, gonadal dysgenesis, and intellectual disability.在一个身材矮小、性腺发育不全和智力障碍的患者中观察到一个小型着丝粒环状X染色体，该染色体缺乏X失活中心。
Because intellectual disability is not a typical feature Turner syndrome explain its presence, with or without other associated physical anomalies, in individuals with a 46,X,r(X) karyotype.由于智力障碍并非特纳综合征的典型特征，请解释其在具有46,X,r(X)核型的个体中出现的原因，无论是否伴有其他相关身体异常。
In a prenatal diagnosis involving a different family, a somewhat larger ring that contains the X inactivation center is detected.在涉及另一个家庭的产前诊断中，检测到一个稍大且包含X失活中心的环状染色体。
What phenotype would you predict for the fetus in this pregnancy?你预测这次妊娠的胎儿会有什么表型？
A baby girl with ambiguous genitalia is found to have 21-hydroxylase deficiency of the salt-wasting type.一名外生殖器模糊的女婴被发现患有失盐型21-羟化酶缺乏症。
What karyotype would you expect to find?你预期会找到什么核型？
What is the disorder?这种疾病是什么？
What genetic counseling would you offer to the parents?你会向父母提供怎样的遗传咨询？
What are the expected clinical consequences of the following deletions?以下缺失的预期临床后果是什么？
If the same amount of DNA is deleted in each case, why might the severity of each be different? a. 46,XX,del(13)(pter→p 11. 1:) b. 46,XY,del(Y)(pter→q 12:) c. 46,XX,del(5)(p 15) d. 46,XX,del(X)(q 23q26) 8.如果在每种情况下删除相同数量的DNA，为什么各自的严重程度可能不同？a. 46,XX,del(13)(pter→p11.1:) b. 46,XY,del(Y)(pter→q12:) c. 46,XX,del(
In genetics clinic, five pregnant women inquire about the risk that their fetus has Down syndrome.[TL:missing]
What are their risks and why? a. 23-year-old mother of a previous child with trisomy 21 b. 41-year-old mother of a previous child with trisomy 21 c. 27-year-old woman whose niece has Down syndrome d. a woman who is a carrier of a 14;21 Robertsonian translocation e. a woman whose husband is a carrier of a 14;21 Robertsonian translocation 9. A young girl with Down syndrome is karyotyped and found to carry a 21q21q translocation.[TL:missing]
With use of standard cytogenetic nomenclature, what is her karyotype? 10. Paracentric inversions generally do not raise the problem of imbalance in offspring.[TL:missing]
PROBLEMS .[TL:missing]