Part 4

PART 4: Patterns of Inheritance and Epigenetics

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Ch7 — Patterns of Single-Gene Inheritance (20) Ch8 — Principles of Clinical Epigenetics (19)

Patterns of Single-Gene Inheritance

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Patterns of Single-Gene Inheritance In Chapter 1 we introduced and briefly characterized the three main categories of ge…
Ch7 — Segment 1
Patterns of Single-Gene Inheritance In Chapter 1 we introduced and briefly characterized the three main categories of genetic disorders – single gene, chromosomal, and complex.单基因遗传的模式 在第一章中，我们介绍并简要描述了三大类遗传疾病——单基因病、染色体病和复杂疾病。
In this chapter the typical patterns of transmission of single-gene disorders are discussed in detail, building on the mechanisms of gene and genome transmission presented generally in Chapters 2 and 3; the emphasis here is on the various inheritance patterns of genetic disease in families.本章详细讨论单基因疾病的典型传递模式，基于第二、三章中普遍介绍的基因和基因组传递机制；重点在于家族中遗传疾病的各种遗传方式。
Later, in Chapter 9, we will examine more complex patterns of inheritance, including multifactorial disorders that result from the interaction between variants at one or more genes, as well as environmental factors.稍后，在第九章中，我们将探讨更复杂的遗传模式，包括由一个或多个基因变异与环境因素相互作用导致的多因子疾病。
OVERVIEW AND CONCEPTS Genotype and Phenotype For autosomal loci (and X-linked loci in females), the genotype of a person at a locus is determined by the alleles occupying that locus on the two homologous chromosomes .概述和概念 基因型和表型 对于常染色体位点（以及女性的X连锁位点），一个人在某个位点的基因型由位于两条同源染色体上该位点的等位基因决定。
Genotype should not be confused with haplotype, which refers to the set of alleles at two or more neighboring loci on one of the two homologous chromosomes.基因型不应与单倍型混淆，单倍型指两条同源染色体之一上两个或多个邻近位点的等位基因集合。
More broadly, the term genotype can refer to all the allele pairs that collectively make up an individual’s genetic constitution across the entire genome.更广泛地，术语“基因型”可指所有等位基因对，它们共同构成个体在整个基因组上的遗传组成。
Phenotype, as described initially in Chapter 3, is the expression of genotype as a morphologic, clinical, cellular, or biochemical trait, which may be clinically observable or may only be detected by blood or tissue testing.表型，如第三章最初所述，是基因型在形态、临床、细胞或生化性状上的表达，可能临床可观察，或仅通过血液或组织检测发现。
The phenotype can be qualitative – such as the presence or absence of a disease – or can be quantitative, such as measured body mass index or a range of blood glucose levels.表型可以是定性的——例如疾病存在与否——也可以是定量的，如测量的体重指数或血糖水平范围。
A phenotype may, of course, be either normal or pathologic in a given individual, but in this book, which emphasizes disorders of medical significance, the focus is on disease phenotypes (i. e., genetic disorders).表型在个体中当然可以是正常的或病理的，但本书强调医学意义的疾病，重点放在疾病表型（即遗传疾病）上。
When a person has a pair of identical alleles at a locus encoded in nuclear DNA, they are said to be homozygous, or a homozygote.当一个人在核DNA编码的位点有一对相同等位基因时，称其为纯合子，或纯合个体。
When the combination of alleles matches to the human reference genome it is referred to as homozygous wild-type.当等位基因组合与人类参考基因组匹配时，称为纯合野生型。
It is important to understand that the reference sequence is merely one possible combination of alleles and that many allelic variants are not associated with disease.重要的是要理解参考序列仅仅是等位基因的一种可能组合，许多等位基因变异与疾病无关。
When two different sets of alleles are present at a locus, a person is heterozygous, or a heterozygote.当某个位点存在两组不同等位基因时，人是杂合子，或杂合个体。
The term compound heterozygote is used to describe a genotype in which two different variants from a reference sequence are present, rather than one wild-type and one variant allele.术语“复合杂合子”用于描述存在两个不同于参考序列的变异，而非一个野生型和一个变异等位基因的基因型。
These terms (homozygous, heterozygous, and compound heterozygous) can be applied either to a person or to a genotype.这些术语（纯合、杂合和复合杂合）可应用于人或基因型。
In the special case in which an XY male has a variant allele for a gene located on the X chromosome, they are referred to as hemizygous.特殊情况下，当XY男性对于X染色体上的基因有一个变异等位基因时，称为半合子。
Mitochondrial DNA is still another special case.线粒体DNA是另一个特殊情况。
In contrast to the two copies of each gene per cell, mitochondrial DNA molecules are typically present in hundreds or thousands of copies per cell (see Chapter 2).与每个细胞中每个基因的两个拷贝不同，线粒体DNA分子通常每个细胞有数百或数千个拷贝（见第二章）。
For this reason, the terms homozygous, heterozygous, and hemizygous are not used to describe genotypes at mitochondrial loci.因此，术语纯合子、杂合子和半合子不用于描述线粒体位点的基因型。
A single-gene disorder is one that is determined primarily by the alleles at a single locus.单基因疾病是主要由单个位点的等位基因决定的疾病。
The known single-gene diseases are maintained in Online Mendelian Inheritance in Man (OMIM; an indispensable resource for medical geneticists created by the late Victor A.已知的单基因疾病收录于《人类孟德尔遗传在线》（OMIM；由已故的Victor A. Mc Kusick创建的医学遗传学家不可或缺的资源）。
Mc Kusick.（注：此句为上一句的延续，但编号[21]单独存在。按照原文，[21]仅为"Mc Kusick."，故翻译为：Mc Kusick。）
Most of these diseases follow one of the classic inheritance patterns in families (autosomal recessive, autosomal dominant, X linked) and are therefore referred to as mendelian because, like the characteristics of the garden peas Gregor Mendel studied, they occur on average in fixed and predictable proportions among the offspring of specific types of matings.这些疾病大多数遵循家族中的经典遗传模式（常染色体隐性、常染色体显性、X连锁），因此称为孟德尔式遗传，因为它们像格雷戈尔·孟德尔研究的豌豆性状一样，在特定婚配类型的后代中平均以固定且可预测的比例出现。
OMIM additionally catalogues mitochondrial disorders, defects due to imprinting, and disorders where the genetic basis is not yet known, as well as genes of known function.OMIM还收录了线粒体疾病、印记缺陷、遗传基础未知的疾病，以及已知功能的基因。
Pathogenic sequence variants in a single gene may produce diverse phenotypic effects in multiple organ systems, with a variety of signs and symptoms occurring at different points during the life span.单个基因的致病性序列变异可能在多个器官系统中产生多样的表型效应，在生命不同阶段出现各种体征和症状。
To cite just one example, individuals with a pathogenic variant in the VHL gene can have hemangioblastomas of the brain, spinal cord, and retina; renal cysts; pancreatic cysts; renal cell carcinoma; pheochromocytoma; endolymphatic tumors of the inner ear; as well as tumors of the epididymis in males or of the broad ligament of the uterus in females.仅举一例，携带VHL基因致病性变异的个体可出现脑、脊髓和视网膜的成血管细胞瘤；肾囊肿；胰腺囊肿；肾细胞癌；嗜铬细胞瘤；内耳内淋巴囊肿瘤；以及男性附睾肿瘤或女性子宫阔韧带肿瘤。
All of these disease manifestations stem from the same single variant.所有这些疾病表现均源于同一个单一变异。
Under these在这些情况下，
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circumstances, the disorder is said to exhibit pleiotropy (from Greek pleion and tropos, “more turns”), and the expressi…
Ch7 — Segment 2
circumstances, the disorder is said to exhibit pleiotropy (from Greek pleion and tropos, “more turns”), and the expression of the gene defect is said to be pleiotropic.在此情况下，该疾病被称为表现出多效性（源自希腊语pleion和tropos，意为“更多转折”），而基因缺陷的表达则被称为多效性的。
Many pleiotropic effects are due to differences in the role of a gene in distinct cell types.许多多效性效应是由于基因在不同细胞类型中作用的差异所致。
With the example of VHL, the impact of pathogenic variants in VHL is cell type specific because the loss of cell cycle regulation gives rise to characteristic problems in specific cell types.以VHL为例，VHL致病性变异的影响具有细胞类型特异性，因为细胞周期调控的丧失在特定细胞类型中引发了特征性问题。
Single-gene disorders affect children disproportionately but not exclusively.单基因病在儿童中不成比例地高发，但并非仅限于儿童。
Serious single-gene disorders affect 1 in 300 neonates and are responsible for an estimated 16% of pediatric hospitalizations.严重的单基因病影响每300名新生儿中的1名，并据估计占儿科住院人数的16%。
Although less than 10% of single-gene disorders manifest after puberty, and only 1% occur after the end of the reproductive period, mendelian disorders are nonetheless important to consider in adult medicine.尽管不到10%的单基因病在青春期后显现，且仅1%发生在生育期结束后，但在成人医学中，孟德尔疾病仍然值得考虑。
There are hundreds of mendelian disorders whose phenotypes include common adult illnesses such as heart disease, stroke, cancer, and diabetes.有数百种孟德尔疾病的表型包括常见成人疾病，如心脏病、中风、癌症和糖尿病。
Although mendelian disorders are by no means the major contributory factor in causing these common diseases in the population at large, they are important in individual patients because of their significance for the health of other family members and because of the availability of genetic testing and detailed management options for many of them.尽管孟德尔疾病绝非导致这些常见疾病在普通人群中发生的主要因素，但它们对个体患者很重要，原因在于它们对其他家庭成员健康的意义，以及其中许多疾病可进行遗传检测并有详细的管理方案。
Penetrance and Expressivity For some genetic conditions, a disease-causing genotype is always fully expressed at birth as an abnormal phenotype.外显率与表现度 对于某些遗传病，一种致病基因型总是在出生时完全表达为异常表型。
Clinical experience, however, teaches that other disorders are not expressed at all or may vary substantially in their signs and symptoms, clinical severity, or age of onset, even among members of a family who all share the same disease-causing genotype.然而，临床经验表明，其他疾病可能完全不表达，或者其症状和体征、临床严重程度或发病年龄存在显著差异，甚至发生在共享相同致病基因型的家庭成员中。
Geneticists use distinct terms to describe such differences in clinical expression.遗传学家使用不同的术语来描述这类临床表达的差异。
Penetrance is the probability that an allele or alleles will have any phenotypic expression at all.外显率是指一个或多个等位基因具有任何表型表达的概率。
When the frequency of expression of a phenotype is less than 100% – that is, when some of those who have the relevant genotype completely fail to express it – the disorder is said to show reduced or incomplete penetrance.当表型表达的频率低于100%——即某些具有相关基因型的人完全未表达该表型——时，该疾病被称为呈现降低或不完全外显率。
Penetrance is all or nothing.外显率是“全或无”的。
It is the percentage of people at any given age with a predisposing genotype who are affected, regardless of the severity.它是指在任何给定年龄，具有易感基因型的人中受到影响的比例，无论严重程度如何。
Penetrance of some disorders is age dependent – that is, it may occur any time, from early in intrauterine development all the way to the postreproductive years.某些疾病的外显率具有年龄依赖性——即可能在任何时间发生，从子宫内发育早期一直到生殖期后。
Some disorders are lethal prenatally, whereas others can be recognized prenatally (e. g., by ultrasonography; see Chapter 18) but are consistent with a live born infant; still others may be recognized only at birth (congenital).有些疾病在产前是致死的，而另一些疾病可以在产前被识别（例如，通过超声检查；见第18章）但能产下活婴；还有一些可能仅在出生时（先天性）被识别。
Other disorders have their onset typically or exclusively in childhood or in adulthood.其他疾病通常在儿童期或成年期发病，或仅在某个时期发病。
It is even possible that two individuals in the same family with the same diseasecausing genotype may develop the disease at very different ages.甚至同一家庭中具有相同致病基因型的两个个体，可能在非常不同的年龄发生该疾病。
In contrast to penetrance, expressivity refers not to the presence or absence of a phenotype but to the severity of expression of that phenotype among individuals with the same disease-causing genotype.与外显率不同，表现度不是指表型的有无，而是指在具有相同致病基因型的个体中，该表型表达的严重程度。
When the severity of disease differs in people who have the same genotype, the phenotype is said to show variable expressivity.当具有相同基因型的人的疾病严重程度不同时，该表型被称为呈现可变表现度。
Even in the same family, two individuals carrying the same pathogenic variants may have some signs and symptoms in common, whereas their other disease manifestations may be quite different, depending on which tissues or organs happen to be affected.即使在同一个家庭中，携带相同致病性变异的两个个体可能有一些共同的症状和体征，而他们的其他疾病表现则可能相当不同，取决于哪些组织或器官恰好受到影响。
The challenge to the clinician caring for these families is to not miss very subtle signs of a disorder in a family member and, as a result, either mistake mild expressivity for lack of penetrance or infer that the individual does not have the disease-causing genotype.照顾这些家庭的临床医生面临的挑战是，不要遗漏家庭成员中非常细微的疾病体征，进而要么将轻微表现度误认为外显率缺失，要么推断该个体不具有致病基因型。
Phenotype Locus 1 Locus 2 A B a b The genotype refers to information encoded in the genome.表型 位点1 位点2 A B a b 基因型指基因组中编码的信息。
Diagram of one pair of homologous chromosomes and two loci on that chromosome, Locus 1 and Locus 2, in an individual who is heterozygous at both loci.这是一个人在两位点均为杂合子时，一对同源染色体及该染色体上位点1和位点2的示意图。
They have alleles A and a at locus 1 and alleles B and b at locus 2.他们在位点1有等位基因A和a，在位点2有等位基因B和b。
The locus 1 genotype is Aa, while the locus 2 genotype is Bb.位点1的基因型是Aa，而位点2的基因型是Bb。
The two haplotypes on these homologous chromosomes are A-B and a-b.这些同源染色体上的两个单体型是A-B和a-b。
(Right) The phenotype is the physical, clinical, cellular, or biochemical manifestation of the genotype, as illustrated here by morphometric aspects of an individual’s face.（右图）表型是基因型的物理、临床、细胞或生化表现，在此以个体面部的形态测量方面为例说明。
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Patterns of Single-Gene Inheritance 111 PEDIGREES Single-gene disorders are characterized by their patterns of transmiss…
Ch7 — Segment 3
Patterns of Single-Gene Inheritance 111 PEDIGREES Single-gene disorders are characterized by their patterns of transmission in families.单基因遗传模式 111 系谱 单基因疾病以其在家族中的传递模式为特征。
A usual first step is to obtain information about the patient’s family history and to summarize the details in the form of a pedigree – a graphical representation of the family tree – with use of standard symbols .通常的第一步是获取患者家族史的信息，并使用标准符号以系谱（家族树的图形表示）的形式总结细节。
Some of these symbols and drawing styles are strongly established, such as the use of a square symbol for a male and a circle for a female.其中一些符号和绘制样式已牢固确立，例如使用正方形符号表示男性，圆形表示女性。
Others vary among users and evolve to accommodate changing needs (e. g., to differentiate sex from gender or Although there is no uniform system of pedigree notation, the symbols used here are commonly used by professionals in the field of genetic counseling. 1Modifiers below symbol: AMAB (assigned male at birth), AFAB (assigned female at birth), UAAB (unassigned at birth), no notation = unknown or not specified 2LMP = last menstrual period (date) 3Note that this symbol may be inappropriate when multiple genotypes are involved (Practice Resource Focused Revision: Standardized pedigree nomenclature update centered on sex and gender inclusivity: A practice resource of the National Society of Genetic Counselors Robin L.其他符号因使用者而异，并随着需求变化而演进（例如，区分生理性别与社会性别或尽管系谱注释没有统一系统，但此处使用的符号在遗传咨询领域专业人员中通用。¹符号下方修饰语：AMAB（出生时指定为男性），AFAB（出生时指定为女性），UAAB（出生时未指定），无注释=未知或未指定 ²LMP=末次月经（日期）³注意，当涉及多种基因型时，此符号可能不适用（实践资源重点修订：以性别与性别包容性为中心的标准系谱命名法更新：美国遗传咨询师学会实践资源 Robin L.
Bennett et al.) J Genet Couns. 2022;00:1–11.Bennett 等）J Genet Couns. 2022;00:1–11.
Male Spontaneous abortion /miscarriage Stillbirth SB Sex or gender unknown or non-binary 1 Female 2 Number of individuals in specified category Affected with phenotype specified in key Segments indicate components of phenotype as specified in key Currently non-expressing carrier (typically for dominant phenotype) Monozygotic twins Dizygotic twins Twins of unknown zygosity?男性 自然流产/流产 死产 SB 性别或社会性别未知或非二元 ¹女性 ²指定类别中的个体数 受键中指定表型影响 线段表示键中指定的表型组分 当前不表达的携带者（通常针对显性表型） 同卵双胞胎 异卵双胞胎 卵性未知双胞胎？
Abortion /termination of pregnancy (TOP) Carrier for recessive phenotype specified in key 3 Marriage or union Proband Consultand P C Union ended Consanguineous union Sibship Adopted out of family Sibship with known genotypes CFTR: F508del/F508del CFTR: +/+ Deceased Pregnancy with information LMP [date]2 P Adopted into family No offspring Infertility [Cause, if known]流产/终止妊娠（TOP） 键中指定的隐性表型携带者 ³婚姻或结合 先证者 咨询者 P C 结合结束 近亲结合 同胞群 被家庭外收养 已知基因型的同胞群 CFTR: F508del/F508del CFTR: +/+ 已故 妊娠伴信息 LMP [日期]² P 被家庭内收养 无后代 不育 [原因，如已知]
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to accommodate assisted reproduction options).
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to accommodate assisted reproduction options).[TL:failed]
How to differentiate phenotype and genotype can be a point for consideration, especially as sequence information becomes more prevalent.[TL:failed]
Many professionals advocate the need for standardization, particularly as computergenerated pedigree drawings become more widespread, but there is not yet one established authority.[TL:failed]
Drawings in this text reflect a variety of current styles of presenting such pedigrees.[TL:failed]
The most important considerations are to be clear and practical and to define the symbols and abbreviations used for the drawing.[TL:failed]
The extended family depicted in such pedigrees is a kindred .[TL:failed]
An affected individual through whom a family is first brought to medical attention (i. e., is ascertained) is the proband, propositus, or index case.[TL:failed]
The person who consults a health professional is referred to as the consultand (or perhaps patient or client) who may or may not themself be affected.[TL:failed]
Probands and consultands are sometimes differentiated on the pedigree with P or C beside their respective arrows.[TL:failed]
A family may have more than one proband if they are ascertained through more than one source.[TL:failed]
Brothers and sisters are called sibs or siblings, and a family of sibs forms a sibship.[TL:failed]
Relatives are classified as first degree (parents, sibs, and offspring), second degree (grandparents and grandchildren, uncles and aunts, nephews and nieces, and half-sibs), or third degree (e. g., first cousins), and so forth, depending on the number of steps in the pedigree between the two relatives.[TL:failed]
Couples who have one or more ancestors in common are consanguineous.[TL:failed]
If the proband is the only affected member in a family, that person is an isolated (or sometimes sporadic) case.[TL:failed]
When there is a definitive diagnosis based on comparisons to other patients, wellestablished patterns of inheritance in other families with the same disorder can often be used as a basis for counseling, even with an isolated case.[TL:failed]
Examining a pedigree is an essential first step in determining the inheritance pattern of a genetic disorder in a family.[TL:failed]
There are, however, situations that may make this difficult to discern in an individual pedigree.[TL:failed]
For example, in a family with a lethal disorder affecting a fetus early in pregnancy, one may observe only multiple miscarriages or reduced fertility.[TL:failed]
For phenotypes with delayed onset, a family may include members who have not yet reached the age at which the disease reveals itself.[TL:failed]
Nonpenetrance or variable expressivity may make it difficult to obtain accurate information about the existence of relatives carrying a pathogenic genotype.[TL:failed]
Family relationships may be inaccurately described.[TL:failed]
Finally, in smaller families, the proband may happen to be the only affected family member, making determination of any inheritance pattern very difficult.[TL:failed]
PATTERNS OF INHERITANCE The patterns of inheritance shown by single-gene disorders in families depend chiefly on two factors: Whether the chromosomal location of the gene locus is on an autosome (chromosomes 1–22), on a sex chromosome (X and Y chromosomes), or in the mitochondrial genome Whether the phenotype is dominant (expressed when only one chromosome carries the pathogenic allele) or recessive (expressed only when both chromosomes of a pair carry pathogenic alleles at a locus) The different patterns of transmission of the autosomes, sex chromosomes, and mitochondria during meiosis result in distinctive inheritance patterns of pathogenic alleles on these different types of chromosome (see Chapter 2).[TL:failed]
Because only one of the two copies of each autosome passes into a single gamete during meiosis, males and females heterozygous for a I II III IV V 1 8 7 6 5 4 3 2 1 2° 4° 4° 1° 1° 1° *2° and *4° 1 2 3 4 6 5 4 3 2 1 1 2 5 6 7 8 9 2° 2° 2° 2° 2° 2° 1° 1° 1° 3° 1° 1° 1° 3° 3 4 Generations are designated with roman numerals; individuals within each generation are specified by arabic numerals above the symbols.[TL:failed]
The proband, III-5(arrow), represents an isolated case of a genetic disorder.[TL:failed]
She has four siblings: III-3, III-4, III-7, and III-8.[TL:failed]
Her partner/spouse is III-6, and they have three children (their F1 progeny).[TL:failed]
The proband has nine first-degree (1°) relatives (her parents, siblings, and offspring), nine second-degree (2°) relatives (grandparents, uncles and aunts, nieces and nephews, and grandchildren), two third-degree (3°) relatives (first cousins), and four fourth-degree (4°) relatives (first cousins once removed).[TL:failed]
IV-3, IV-5, and IV-6 are second cousins of IV-1 and IV-2.[TL:failed]
IV-7 and IV-8, whose parents are consanguineous, are doubly related to the proband: second-degree relatives through their father and fourth-degree relatives through their mother.[TL:failed]
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Patterns of Single-Gene Inheritance 113 pathogenic allele on an autosome have a 50% chance of passing that allele on to …
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Patterns of Single-Gene Inheritance 113 pathogenic allele on an autosome have a 50% chance of passing that allele on to any offspring, regardless of the child’s sex.单基因遗传模式 113 常染色体上的致病等位基因有50%的概率传递给任何子代，不论子女性别。
Pathogenic alleles on the X chromosome, however, are not distributed equally to sons and daughters.然而，X染色体上的致病等位基因并非均等地传递给儿子和女儿。
Males pass their Y chromosome to their sons and their X to their daughters; they therefore cannot pass an allele on the X chromosome to their sons and always pass the allele to their daughters (unless it is at one of the pseudoautosomal loci; see Chapter 6).男性将其Y染色体传给儿子，X染色体传给女儿；因此，他们无法将X染色体上的等位基因传给儿子，而总是将该等位基因传给女儿（除非位于假常染色体区域；参见第6章）。
Because mitochondria are inherited from the mother only, regardless of the sex of the offspring, variants in the mitochondrial genome are not inherited according to a mendelian pattern.由于线粒体仅来自母亲遗传，无论子代性别如何，线粒体基因组中的变异不遵循孟德尔遗传模式。
Autosomal, X-linked, and mitochondrial inheritance will be discussed in the rest of the chapter that follows.常染色体、X连锁和线粒体遗传将在本章后续部分讨论。
Dominant and Recessive Traits Autosomal Loci As classically defined, a phenotype is recessive if it is expressed only in homozygotes or compound heterozygotes, all of whom lack a wild-type allele, and never in heterozygotes, who do have a wild-type allele.显性与隐性性状 常染色体位点 经典定义中，若表型仅表达于纯合子或复合杂合子（均缺乏野生型等位基因），而从不表达于具有野生型等位基因的杂合子，则该表型为隐性。
In contrast, a dominant inheritance pattern occurs when a phenotype is expressed in heterozygotes as well as in homozygotes (or compound heterozygotes).相反，当表型在杂合子以及纯合子（或复合杂合子）中均表达时，则为显性遗传模式。
For the vast majority of inherited dominant diseases, homozygotes or compound heterozygotes for pathogenic alleles at autosomal loci are more severely affected than are heterozygotes, an inheritance pattern known as incompletely dominant (or semidominant).对于绝大多数遗传性显性疾病，常染色体位点上致病等位基因的纯合子或复合杂合子比杂合子受累更严重，这种遗传模式被称为不完全显性（或半显性）。
Very few diseases are known in which homozygotes (or compound heterozygotes) show the same phenotype as heterozygotes; such a disorder is referred to as a pure dominant disease.已知极少数疾病中纯合子（或复合杂合子）表现出与杂合子相同的表型；这类疾病被称为纯显性疾病。
Finally, if phenotypic expression of both alleles at a locus occurs in a compound heterozygote, inheritance is termed codominant.最后，若在复合杂合子中某位点的两个等位基因均有表型表达，则遗传称为共显性。
ABO Blood Group.ABO血型。
One medically important trait that demonstrates codominant expression is the ABO blood group system important in blood transfusion and tissue transplantation.一个体现共显性表达的医学重要性状是ABO血型系统，其在输血和组织移植中至关重要。
The A, B, and O alleles at the ABO locus form a three-allele system in which two alleles (A and B) govern expression of either the A or B carbohydrate antigen on the surface of red cells as a codominant trait; a third allele (O) results in expression of neither the A nor the B antigen and is recessive.ABO位点上的A、B和O等位基因构成三等位基因系统，其中两个等位基因（A和B）以共显性方式调控红细胞表面A或B碳水化合物抗原的表达；第三个等位基因（O）导致既不表达A抗原也不表达B抗原，为隐性。
The difference between the A and B antigen is which of two different sugar molecules makes up the terminal sugar on a cell surface glycoprotein called H.A抗原与B抗原的区别在于两种不同的糖分子中哪一种构成了称为H的细胞表面糖蛋白上的末端糖。
Whether the A or B form of the glycoprotein is made is specified by an enzyme encoded by the ABO gene that adds one or the other sugar molecule to the H antigen, depending on which version of the enzyme is encoded by alleles at the ABO locus.糖蛋白的A型或B型由ABO基因编码的酶决定，该酶将其中一种糖分子添加到H抗原上，具体取决于ABO位点等位基因编码的酶版本。
There are, therefore, four phenotypes possible: O, A, B, and AB ( Type A individuals have antigen A on their red blood cells, type B individuals have antigen B, type AB individuals have both antigens, and type O individuals have neither.因此，有四种可能的表型：O、A、B和AB（A型个体红细胞上有A抗原，B型个体有B抗原，AB型个体有两种抗原，O型个体则都没有。
A feature of the ABO groups not shared by other blood group systems is the reciprocal relationship, in an individual, between the antigens present on the red blood cells and the antibodies in the serum (see When the red blood cells lack antigen A, the serum contains anti-A antibodies; when the cells lack antigen B, the serum contains anti-B.ABO血型组的一个其他血型系统不具备的特征是个体内红细胞上存在的抗原与血清中抗体之间的互反关系（参见：当红细胞缺乏A抗原时，血清中含有抗A抗体；当细胞缺乏B抗原时，血清中含有抗B。
Formation of anti-A and anti-B antibodies in the absence of prior blood transfusion is believed to be a response to the natural occurrence of A-like and B-like antigens in the environment (e. g., in bacteria).在没有既往输血史的情况下产生抗A和抗B抗体被认为是对环境中（例如细菌中）天然存在的A样和B样抗原的反应。
X-Linked Loci For X-linked disorders, a condition expressed only in hemizygotes and never in heterozygotes has traditionally been referred to as an X-linked recessive, whereas a phenotype that is always expressed in heterozygotes as well as in hemizygotes has been called X-linked dominant.X连锁位点 对于X连锁疾病，仅在半合子中表达而从不表达于杂合子的病症传统上称为X连锁隐性，而始终在杂合子和半合子中均表达的表型则称为X连锁显性。
Because of epigenetic regulation of X-linked gene expression in carrier females, due to X chromosome inactivation (introduced in Chapters 3 and 6), it can be difficult to determine phenotypically whether a disease with an X-linked inheritance pattern is dominant or recessive.由于携带者女性中X连锁基因表达的表观遗传调控（由于X染色体失活，在第3章和第6章介绍），从表型上判断具有X连锁遗传模式的疾病是显性还是隐性可能很困难。
Some geneticists have, therefore, chosen not to use these terms when describing the inheritance of X-linked disease.因此，一些遗传学家选择在描述X连锁疾病遗传时不再使用这些术语。
Strictly speaking, the terms dominant and recessive refer to the inheritance pattern of a phenotype rather than to the alleles responsible for that phenotype.严格来说，显性和隐性这两个术语指的是表型的遗传模式，而非导致该表型的等位基因。
Similarly, a gene is not dominant or recessive; it is the phenotype produced by a particular pathogenic allele in that gene that shows dominant or recessive inheritance.同样，基因本身并非显性或隐性；而是该基因中特定致病等位基因所产生的表型表现出显性或隐性遗传。
AUTOSOMAL PATTERNS OF MENDELIAN INHERITANCE Autosomal Recessive Inheritance Autosomal recessive disease occurs only in individuals with pathogenic variants on both inherited alleles and no wildtype allele.孟德尔遗传的常染色体模式 常染色体隐性遗传 常染色体隐性遗传病仅发生于两个遗传等位基因均存在致病变异且无野生型等位基因的个体。
Such homozygotes or compound heterozygotes RBC, Red blood cell.此类纯合子或复合杂合子 RBC，红细胞。
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must have inherited a pathogenic allele from each parent, each of whom is (barring rare exceptions that we will consider…
Ch7 — Segment 6
must have inherited a pathogenic allele from each parent, each of whom is (barring rare exceptions that we will consider later) a heterozygote for that allele.必须从父母双方各继承一个致病等位基因，而父母双方（除了我们稍后将考虑的罕见例外）均为该等位基因的杂合子。
When a disorder shows recessive inheritance, the pathogenic variant responsible generally reduces or eliminates the function of the gene product: a so-called loss-of-function mutation.当疾病表现为隐性遗传时，致病变异通常会降低或消除基因产物的功能，即所谓的功能缺失突变。
For example, many recessive diseases are caused by variants that impair or eliminate the function of an enzyme.例如，许多隐性遗传病是由损害或消除酶功能的变异引起的。
In a heterozygote, a remaining normal gene copy is able to compensate for the pathogenic allele and prevent the disease from occurring.在杂合子中，剩余的一个正常基因拷贝能够补偿致病等位基因，从而防止疾病发生。
However, when no wild-type allele is present, as in homozygotes or compound heterozygotes, disease occurs.然而，当不存在野生型等位基因时，例如在纯合子或复合杂合子中，疾病就会发生。
Disease mechanisms and examples of recessive conditions are discussed in detail in Chapters 12 and 13.疾病机制和隐性遗传病的例子将在第12章和第13章中详细讨论。
Autosomal recessive disorders may appear whenever two parents are at least carriers for the condition, here with the genotype R/r ( Carriers are unaffected heterozygotes.常染色体隐性遗传病可在父母双方至少为该病携带者时出现，这里基因型为R/r（携带者是不受影响的杂合子。
In the common case where we consider two carrier parents, the risk of transmission of disease is 25%, since each parent passes an allele at random to their offspring.在常见的双亲均为携带者的情况下，疾病传递的风险为25%，因为每位父母随机向子代传递一个等位基因。
Autosomal recessive disorders may also occur when one parent is a carrier and the other parent has the disease (genotype r/r).当一方父母为携带者而另一方父母患病（基因型r/r）时，也可能出现常染色体隐性遗传病。
In this case the risk of transmission is 50% since the affected parent must transmit a pathogenic allele and the carrier parent transmits the pathogenic allele 50% of the time.在这种情况下，传递风险为50%，因为患病父母必定传递一个致病等位基因，而携带者父母有50%的概率传递致病等位基因。
Autosomal recessive disorders will always appear in offspring when both parents are affected by the identical condition, since neither parent has a wildtype allele to transmit.当父母双方均患有相同疾病时，子代总会表现出常染色体隐性遗传病，因为父母双方均无野生型等位基因可传递。
Often in autosomal recessive disorders, the proband may be the only affected family member, but if any others are affected, they are usually in the same sibship and not elsewhere in the kindred .在常染色体隐性遗传病中，先证者可能是唯一受影响的家庭成员，但若还有其他受影响者，通常出现在同一同胞群而非家族中的其他位置。
Sex-Influenced Autosomal Recessive Disorders Because males and females both have the same complement of autosomes, autosomal recessive disorders generally show the same frequency and severity in males and females.性别影响的常染色体隐性遗传病：由于男性和女性具有相同的常染色体组成，常染色体隐性遗传病通常在男性和女性中显示出相同的频率和严重程度。
There are, however, exceptions.然而，也存在例外情况。
Some autosomal recessive diseases demonstrate a sex-influenced phenotype – that is, the disorder is expressed in both sexes but with different frequencies or severity.一些常染色体隐性遗传病表现出受性别影响的表型，即该疾病在两性中均有表达，但频率或严重程度不同。
For example, hereditary hemochromatosis is an autosomal recessive phenotype that is 5 to 10 times more common in males than in females (Case 20).例如，遗传性血色病是一种常染色体隐性表型，其在男性中的发病率是女性的5至10倍（病例20）。
Affected individuals have enhanced absorption of dietary iron that can lead I II III IV Filled symbols represent individuals affected with the trait.受影响个体对膳食铁的吸收增强，可能导致I II III IV 填充符号代表受该性状影响的个体。
Those with dots represent obligate carriers of the variant allele for the recessive trait but are unaffected.带有圆点的个体代表该隐性性状变异等位基因的必然携带者，但不受影响。
Many others in the pedigree also have significant likelihood to be carriers.系谱中的许多其他个体也有很大可能成为携带者。
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Patterns of Single-Gene Inheritance 115 to iron overload and serious damage to the heart, liver, and pancreas.
Ch7 — Segment 7
Patterns of Single-Gene Inheritance 115 to iron overload and serious damage to the heart, liver, and pancreas.单基因遗传模式115至铁过载及心脏、肝脏和胰腺的严重损伤。
The lower incidence of the clinical disorder in homozygous females is believed to be due to their lower dietary iron intake, lower alcohol usage, and increased iron loss through menstruation.纯合女性临床疾病发生率较低被认为是因为她们饮食中铁摄入量较低、饮酒量较少以及通过月经增加的铁流失。
Gene Frequency and Carrier Frequency Pathogenic alleles responsible for a recessive disorder are generally rare, so most people will not have even one such copy.基因频率与携带者频率 导致隐性疾病发生的致病等位基因通常罕见，因此大多数人连一份这样的拷贝都没有。
Because an autosomal recessive disorder must be inherited from both parents, the risk that any carrier will have an affected child depends partly on the chance that their partner is also a carrier of a pathogenic allele for the condition.由于常染色体隐性遗传病必须从父母双方遗传，因此任何携带者生育患病子女的风险部分取决于其伴侣是否也是该病致病等位基因的携带者。
Thus, knowledge of the carrier frequency of a disease in the population is clinically important for genetic counseling.因此，了解疾病在人群中的携带者频率对于遗传咨询具有临床重要性。
As an example, the most common autosomal recessive disorder in individuals of European ancestry is cystic fibrosis (CF) (Case 12), caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see Chapter 13).例如，欧洲裔个体中最常见的常染色体隐性遗传病是囊性纤维化（CF）（病例12），由囊性纤维化跨膜传导调节因子（CFTR）基因的致病变异引起（见第13章）。
Among this population, ~1 in 2500 individuals has two pathogenic CFTR alleles and has the disease, from which we can infer that 1 in 24 individuals is a carrier.在该人群中，约每2500人中有一人携带两个致病CFTR等位基因并患有该疾病，由此可推断每24人中有一人为携带者。
(How one calculates heterozygote frequencies in autosomal recessive conditions will be addressed in Chapter 10.) Pathogenic variants may be transmitted from generation to generation without appearing in a homozygous or compound heterozygous state and causing overt disease.（关于如何计算常染色体隐性疾病中的杂合子频率将在第10章讨论。）致病变异可能代代相传，却未以纯合或复合杂合状态出现并引起明显疾病。
The presence of such hidden recessive genes is not revealed unless the carrier has children with someone who also carries a pathogenic allele at the CFTR locus and both deleterious alleles are inherited.此类隐性基因的存在不会被揭示，除非携带者与同样在CFTR基因座上携带致病等位基因的人生育子女，并且两个有害等位基因均被遗传。
Estimates of the number of deleterious alleles in each of our genomes range from 50 to 200, based on examining an individual’s complete exome or genome sequence for clearly deleterious variants in the coding regions of the genome (see Chapter 4).根据对个体完整外显子组或基因组序列中编码区明显有害变异的检查，每个人基因组中有害等位基因数量的估计范围在50到200之间（见第4章）。
This estimate is imprecise, however.然而，这一估计并不精确。
It may be an underestimate because it does not include variants whose deleterious effect is not obvious from a simple examination of the DNA sequence.它可能被低估，因为其不包括那些仅通过简单DNA序列检查无法明确其有害效应的变异。
Alternatively, it may be an overestimate because it includes variants in many genes that are not known to cause disease.或者，它可能被高估，因为其包括了众多尚未知可导致疾病的基因中的变异。
Consanguinity Because most pathogenic variants are generally uncommon in the population, people with rare autosomal recessive disorders are often compound heterozygotes rather than true homozygotes.近亲结婚 由于大多数致病变异在人群中通常不常见，患有罕见常染色体隐性疾病的人往往是复合杂合子而非真正的纯合子。
One well-recognized exception to this rule occurs when an affected individual inherits the exact same pathogenic allele from both parents because the parents are consanguineous (i. e., they are related and carry the identical allele inherited from a common ancestor).该规则的一个公认例外是，当患病个体从父母双方继承完全相同的致病等位基因时，这是因为父母为近亲结婚（即，他们有亲缘关系并携带从共同祖先继承的相同等位基因）。
Consanguinity in the parents of a patient with a genetic disorder is strong evidence (although not proof) for the autosomal recessive inheritance of that condition.遗传病患者的父母存在近亲结婚是支持该病为常染色体隐性遗传的有力证据（尽管并非确证）。
For example, the disorder in the pedigree in , a very rare autosomal recessive condition of DNA repair (see Chapter 16), more than 20% of cases occur among the offspring of first cousins.例如，在系谱中的疾病——一种非常罕见的常染色体隐性DNA修复疾病（见第16章）中，超过20%的病例出现在表亲结婚的后代中。
In contrast, in more common recessive conditions, most children are born to ostensibly unrelated persons, each of whom happens by chance to be a carrier.相比之下，在较常见的隐性疾病中，大多数患病子女出生于外表无亲缘关系的夫妇，每人均碰巧是携带者。
Thus, most affected persons with a relatively common disorder, such as phenylketonuria, do not have consanguineous parents because pathogenic variants are common in the general population.因此，大多数患有相对常见疾病（如苯丙酮尿症）的患者并非近亲结婚所生，因为致病变异在普通人群中较为常见。
How consanguinity is measured is described in Chapter 10.如何衡量近亲结婚程度在第10章中描述。
The genetic risk to the offspring of related people is not as great as is sometimes imagined.有亲缘关系的人的后代所面临的遗传风险并不像有时想象的那样大。
For first cousins, the absolute risk to offspring, including not only known autosomal recessive diseases but also stillbirth, neonatal death, and congenital malformation, is 3% to 5%, approximately double the overall background risk of 2% to 3% for offspring born to an unrelated couple (see Chapter 17).对于表亲而言，其后代面临的绝对风险——不仅包括已知的常染色体隐性疾病，还包括死产、新生儿死亡和先天性畸形——为3%至5%，大约是无关夫妇后代总体背景风险（2%至3%）的两倍（见第17章）。
Because consanguinity can be seen in any population, it is always important to ascertain in every family.由于近亲结婚可见于任何人群，因此在每个家族中查明这一点始终很重要。
CHARACTERISTICS OF AUTOSOMAL RECESSIVE INHERITANCE An autosomal recessive phenotype, if not isolated, is typically seen only in the sibship of the proband, not in parents, offspring, or other relatives.常染色体隐性遗传的特征 常染色体隐性表型，若非孤立发生，通常仅见于先证者的同胞中，而非父母、子女或其他亲属。
For most autosomal recessive traits, males and females are equally likely to be affected.对于大多数常染色体隐性性状，男性和女性受影响的可能性相同。
Parents of an affected child are asymptomatic carriers of pathogenic alleles (obligate carriers).患病子女的父母是致病等位基因的无症状携带者（必然携带者）。
The parents of the affected person may in some cases be consanguineous.在某些情况下，患病个体的父母可能为近亲结婚。
This is especially likely if the gene responsible for the condition is rare in the population.如果导致该病的基因在人群中罕见，这种情况尤其可能发生。
I II III IV Arrow indicates the proband.I II III IV 箭头指示先证者。
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The recurrence risk for each sib of the proband is 1 in 4 (25%).
Ch7 — Segment 8
The recurrence risk for each sib of the proband is 1 in 4 (25%).先证者每位同胞的再发风险为1/4（25%）。
Unaffected sibs of proband have a ⅔ chance of being carriers.先证者的未患病同胞有2/3的概率为携带者。
Autosomal Dominant Inheritance More than half of all known mendelian disorders are inherited as autosomal dominant traits.常染色体显性遗传 所有已知孟德尔疾病中超过一半以常染色体显性性状方式遗传。
The incidence of some autosomal dominant disorders can be high.某些常染色体显性疾病的发病率可能较高。
For example, adult polycystic kidney disease (Case 37) occurs in 1 in 1000 individuals in the United States.例如，成人型多囊肾病（病例37）在美国的发病率为1/1000。
Other autosomal dominant disorders show a high frequency only in certain populations from specific geographic areas (e. g., the frequency of familial hypercholesterolemia [Case 16] affects 1 in 100 for Afrikaner populations in South Africa; myotonic dystrophy affects 1 in 550 in the Charlevoix and Saguenay–Lac Saint Jean regions of northeastern Quebec).其他常染色体显性疾病仅在特定地理区域的某些人群中显示高频率（例如，家族性高胆固醇血症[病例16]在南非阿非利卡人中的发病率为1/100；强直性肌营养不良在魁北克东北部的沙勒瓦和萨格奈-圣让湖地区的发病率为1/550）。
The burden of autosomal dominant disorders is further increased because of their hereditary nature; when they are transmitted through families they raise medical and even social problems, not only for individuals but also for whole kindreds, often through many generations.常染色体显性疾病的负担因其遗传性而进一步增加；当它们在家族中传递时，不仅对个体而且对整个家族，常常历经多代，引发医学甚至社会问题。
The risk and severity of dominantly inherited disease in the offspring depend on whether one or both parents are affected and whether the trait is a pure dominant or is incompletely dominant.后代中显性遗传病的风险和严重程度取决于父母一方或双方是否患病，以及该性状是纯显性还是不完全显性。
There are a number of ways that one pathogenic allele can cause a dominantly inherited trait to occur in a heterozygote despite the presence of a normal allele.尽管存在正常等位基因，一个致病等位基因有多种方式可在杂合子中引起显性遗传性状的发生。
Disease mechanisms in various dominant conditions are discussed in Chapter 12.各种显性疾病的疾病机制在第12章中讨论。
Denoting D as the pathogenic variant and d as the wild-type allele, the parents of children with an autosomal dominant disease can be two heterozygotes (D/d) or, more frequently, a heterozygote (D/d) and a homozygote for a normal allele (d/d).用D表示致病变异，d表示野生型等位基因，常染色体显性疾病患儿的父母可以是两个杂合子（D/d），或者更常见的是一个杂合子（D/d）和一个正常等位基因纯合子（d/d）。
As seen in In the population as a whole, then, the offspring of D/d by d/d parents are ~50% D/d and 50% d/d.如全人群中所见，D/d与d/d父母的后代约为50%为D/d，50%为d/d。
Of course, each pregnancy is an independent event, not governed by the outcome of previous pregnancies.当然，每次妊娠是独立事件，不受先前妊娠结果的影响。
Thus, within a family, the distribution of affected and unaffected children may be quite different from the theoretic expected ratio of 1:1, especially if the sibship is small.因此，在一个家庭内，患病和未患病子女的分布可能与理论期望的1:1比例相差很大，尤其是同胞组较小时。
Typical autosomal dominant inheritance can be seen in the pedigree of a family with a dominantly inherited form of hereditary deafness .在具有显性遗传性耳聋形式的家系图谱中可见典型的常染色体显性遗传。
In practice, homozygotes for dominant phenotypes are not often seen, but the offspring of two affected individuals with the genotype D/d could have a D/D genotype 25% of the time.在实践中，显性表型的纯合子并不常见，但两个基因型为D/d的患病个体的后代有25%的概率为D/D基因型。
The potential to observe individuals with the D/D genotype may also be limited if the phenotype causes early lethality (see the description of incompletely dominant inheritance later).如果表型导致早期致死，观察到D/D基因型个体的可能性也可能受限（见后文不完全显性遗传的描述）。
Pure Dominant Inheritance As mentioned earlier, very few human disorders demonstrate a purely dominant pattern of inheritance.纯显性遗传 如前所述，极少数人类疾病表现出纯显性遗传模式。
Even Huntington disease (Case 24), which is frequently considered to be a pure dominant because the nature and severity of symptoms in heterozygotes and homozygotes is similar, appears to have a somewhat accelerated time course from onset to death in homozygous individuals, compared with that of heterozygotes.即使是亨廷顿病（病例24），常因其杂合子和纯合子症状的性质和严重程度相似而被视为纯显性，但纯合子个体从发病到死亡的时间进程似乎比杂合子有所加速。
Incompletely Dominant Inheritance As introduced in Chapter 4, achondroplasia (Case 2) is an incompletely dominant skeletal disorder (shortlimbed dwarfism and large head) caused by certain variants in the fibroblast growth factor receptor 3 gene (FGFR3).不完全显性遗传 如第4章所述，软骨发育不全（病例2）是一种不完全显性骨骼疾病（短肢侏儒症和大头），由成纤维细胞生长因子受体3基因（FGFR3）的某些变异引起。
Most individuals with achondroplasia have大多数软骨发育不全患者有
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Patterns of Single-Gene Inheritance 117 I II III IV I II III 2 3 I II FGFR3 arg 248cys A B C Pedigree showing inheritanc…
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Patterns of Single-Gene Inheritance 117 I II III IV I II III 2 3 I II FGFR3 arg 248cys A B C Pedigree showing inheritance of achondroplasia, an incompletely dominant (or semidominant) trait.单基因遗传模式 117 I II III IV I II III 2 3 I II FGFR3 arg 248cys A B C 显示软骨发育不全（一种不完全显性或半显性性状）遗传的家系图。
(C) Pedigree showing a sporadic case of thanatophoric dwarfism, a genetic lethal, in the proband (arrow). normal intelligence and lead normal lives within their physical capabilities.(C) 显示先证者（箭头所示）中致死性侏儒症（一种遗传致死性疾病）散发案例的家系图；患者智力正常，并能在其身体能力范围内过着正常生活。
A pedigree with two parents heterozygous for the most common pathogenic variant that causes achondroplasia is shown in females, it can also be transmitted directly from father to son, showing that it is autosomal, not X linked.一个父母双方均为导致软骨发育不全的最常见致病突变杂合子的家系，在女性中可见该突变，也可直接从父亲传给儿子，表明其为常染色体遗传，而非X连锁。
For disorders in which affected males do not reproduce, however, it is not always easy to distinguish sexlimited autosomal inheritance from X-linked inheritance, because the critical evidence—absence of male-to-male transmission, cannot be provided.然而，对于受累男性不生育的疾病，区分限性常染色体遗传与X连锁遗传并不总是容易的，因为关键证据——男性间传递的缺失——无法提供。
In that case, other lines of evidence, particularly gene mapping to learn whether the responsible gene maps to the X chromosome or to an autosome (see Chapter 11), can determine the pattern of inheritance and the consequent recurrence risk (1).在这种情况下，其他证据线索，特别是通过基因定位确定致病基因位于X染色体还是常染色体（见第11章），可以判定遗传模式及由此产生的再发风险（1）。
I II III This autosomal dominant disorder can be transmitted by affected males or by unaffected carrier females.I II III 这种常染色体显性遗传病可由受累男性或未受累携带者女性传递。
Male-to-male transmission shows that inheritance is autosomal, not X linked.男性间传递表明遗传方式为常染色体遗传，而非X连锁遗传。
Transmission of the trait through carrier females shows that inheritance cannot be Y linked.通过携带者女性传递该性状表明遗传方式不可能是Y连锁遗传。
Arrow indicates proband.箭头指示先证者。
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A B Upper part of body.
Ch7 — Segment 10
A B Upper part of body.A B 上半身。
(B) Lower part of body.(B) 下半身。
(From Kelikian H: Congenital deformities of the hand and forearm, Philadelphia, 1974, WB Saunders.) 1 CHARACTERISTICS OF AUTOSOMAL DOMINANT INHERITANCE The phenotype usually appears in every generation, each affected person having an affected parent.(摘自 Kelikian H: Congenital deformities of the hand and forearm, Philadelphia, 1974, WB Saunders.) 1 常染色体显性遗传的特征 表型通常出现在每一代，每个受累个体都有一个受累的父母。
Exceptions or apparent exceptions to this rule in clinical genetics are (1) cases originating from new mutations and (2) cases in which the disorder is not expressed (nonpenetrant) or is expressed only subtly in a person who has inherited the responsible pathogenic allele.临床遗传学中该规则的例外或看似例外的情况包括：(1) 源于新生突变的病例，以及(2) 疾病未表达（不完全外显）或仅在遗传了致病等位基因的个体中表达细微的病例。
Any child of an affected parent has a 50% risk for inheriting the trait.受累父母的每个子女有50%的风险遗传该性状。
This is true for most families, in which the other parent is phenotypically normal.这适用于大多数家庭，其中另一父母表型正常。
Because statistically each family member is the result of an “independent event,” wide deviation from the expected 1:1 ratio may occur by chance in a single family.由于统计学上每个家庭成员是“独立事件”的结果，单个家庭中可能偶然出现与预期1:1比例的较大偏差。
Phenotypically normal family members do not transmit the phenotype to their children.表型正常的家庭成员不会将该表型传递给子女。
Failure of penetrance or subtle expression of a condition may lead to apparent exceptions to this rule.外显不全或疾病的细微表达可能导致该规则的明显例外。
Males and females are equally likely to transmit the phenotype, to children of either sex.男性和女性传递该表型给任一性别子女的概率相同。
In particular, maleto-male transmission can occur, and males can have unaffected daughters.特别是，男性对男性的传递可能发生，且男性可以有未受累的女儿。
A significant proportion of isolated cases are sporadic due to new mutation.显著比例的孤立病例是由于新生突变引起的散发。
The less the fitness, the greater is the proportion of cases due to new mutation.适应度越低，因新生突变所致的病例比例越高。
Effect of Incomplete Penetrance, Variable Expressivity, and New Mutations on Autosomal Dominant Inheritance Patterns Some of the difficulties raised by incomplete penetrance in fully understanding the inheritance of a disease phenotype are demonstrated by the split-hand/foot malformation, a type of ectrodactyly that can be caused by pathogenic variants in the DLX5 gene .不完全外显、可变表达度和新生突变对常染色体显性遗传模式的影响 分裂手/足畸形（一种由DLX5基因致病性变异引起的缺指畸形）展示了不完全外显在完全理解疾病表型遗传时所带来的部分困难。
The split-hand malformation originates in the sixth or seventh week of development, when the hands and feet are forming.分裂手畸形发生于发育的第6或第7周，即手和足形成时。
Lack of penetrance in pedigrees of split-hand malformation can lead to apparent skipping of generations.分裂手畸形家系中外显不全可导致明显的世代跳跃。
This complicates genetic counseling because an atrisk person with normal hands may, nevertheless, carry a pathogenic variant associated with the condition and, thus, be capable of having children who are affected. .这使得遗传咨询复杂化，因为具有正常手部表现的高风险个体仍可能携带与该疾病相关的致病性变异，从而可能生育受累子女。
Using this pedigree information to calculate conditional probabilities (as discussed further in Chapter 17), one can calculate that the risk that the consultant might herself be a nonpenetrant carrier is 17% and her chance of having a child with the abnormality is therefore ~7% (carrier risk × the risk for transmission × penetrance, or 17% × 50% × 80%).利用该家系信息计算条件概率（如第17章进一步讨论），可以算出咨询者本人可能是不完全外显携带者的风险为17%，因此她生育异常子女的概率约为7%（携带者风险 × 传递风险 × 外显率，即17% × 50% × 80%）。
An autosomal dominant inheritance pattern may also be obscured by variable expressivity.常染色体显性遗传模式也可能被可变表达度所掩盖。
Neurofibromatosis 1 (NF1), a common disorder of the nervous system, demonstrates both age-dependent penetrance and variable expressivity in a single family.神经纤维瘤病1型（NF1）是一种常见的神经系统疾病，在单个家庭中同时表现出年龄依赖性外显率和可变表达度。
Some adults may have only multiple flat, irregular pigmented skin lesions, known as café au lait spots, and small benign tumors (hamartomas) called Lisch nodules on the iris of the eye.一些成人可能仅有多个扁平的、不规则的色素性皮肤病变（称为咖啡牛奶斑）以及虹膜上称为Lisch结节的小型良性肿瘤（错构瘤）。
Other family members can have these signs as well as multiple benign fleshy tumors (neurofibromas) in the skin.其他家庭成员可能同时具有这些体征以及皮肤内多个良性有蒂肿瘤（神经纤维瘤）。
Still others may have a much more severe phenotype, with intellectual disability, diffuse plexiform neurofibromas, or malignant tumors of nervous system or muscle in addition to the café au lait spots, Lisch nodules, and neurofibromas.还有一些人可能表现更严重的表型，除咖啡牛奶斑、Lisch结节和神经纤维瘤外，还伴有智力残疾、弥漫性丛状神经纤维瘤或神经系统或肌肉的恶性肿瘤。
Unless one looks specifically for mild manifestations of the disease in the relatives of the proband, heterozygous carriers may be incorrectly classified as unaffected, noncarriers.除非专门寻找先证者亲属中疾病的轻微表现，否则杂合携带者可能被错误归类为未受累的非携带者。
Furthermore, the signs of NF1 may require many years to develop.此外，NF1的体征可能需要多年才能显现。
For example, in the newborn period, less than half of all affected newborns show even the most subtle sign of the disease: an increased incidence of café au lait spots.例如，在新生儿期，所有受累新生儿中不足一半表现出该疾病最细微的体征：咖啡牛奶斑发生率增加。
Eventually, however, multiple café au lait spots and Lisch nodules do appear, so that by adulthood, heterozygotes always demonstrate some sign of the disease.然而，最终多数咖啡牛奶斑和Lisch结节确实会出现，因此到成年时，杂合子总会显示出该疾病的某些体征。
The challenges for diagnosis and genetic counseling in NF1 are presented in (Case 34).NF1诊断和遗传咨询面临的挑战见（病例34）。
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Patterns of Single-Gene Inheritance 119 Finally, in classic autosomal dominant inheritance, every affected person in a p…
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Patterns of Single-Gene Inheritance 119 Finally, in classic autosomal dominant inheritance, every affected person in a pedigree has an affected parent, who also has an affected parent, and so on, as far back as the disorder can be traced .单基因遗传模式 119 最后，在经典常染色体显性遗传中，家系中的每个患病个体都有一个患病的父母，该父母也有患病的父母，如此回溯，直至该疾病可追溯的最远代。
In fact, however, many dominant conditions of medical importance occur because of a spontaneous, de novo mutation in a gamete inherited from a noncarrier parent .然而事实上，许多具有医学重要性的显性状况是由于从非携带者父母遗传的配子中发生自发的、新生突变所致。
An individual with an autosomal dominant disorder caused by a new mutation will look like an isolated case, and his or her parents, aunts and uncles, and cousins will all be unaffected noncarriers.由新突变引起的常染色体显性遗传病个体表现为散发病例，其父母、叔伯姑舅及堂表亲均未患病且为非携带者。
This person will still be at risk for passing the altered allele down to his or her own children, however.然而，此人仍有将突变等位基因传递给其子女的风险。
Once a new mutation has arisen, the variant allele will be transmitted to future generations following standard principles of inheritance; as we discuss in the next section, its survival in the population depends on the fitness of persons carrying it.一旦新突变发生，变异等位基因将按照标准遗传原理传递给后代；正如我们在下一节讨论的，其在群体中的存续取决于携带者的适合度。
Relationship Between New Mutation and Fitness in Autosomal Dominant Disorders In many disorders, whether a condition demonstrates an obvious pattern of transmission in families depends on whether individuals affected by the disorder can reproduce.常染色体显性遗传病中新生突变与适合度的关系 在许多疾病中，一个状况是否表现出明显的家族传递模式取决于患病个体能否生育。
Geneticists coined the term fitness as a measure of the impact of a condition on reproduction.遗传学家创造了“适合度”这一术语，用以衡量疾病对生殖的影响。
Fitness is defined as the ratio of the number of offspring of individuals affected with the condition who survive to reproductive age, compared to the number of offspring of individuals who do not carry the pathogenic allele.适合度定义为患病个体存活至生育年龄的后代数量与非致病等位基因携带者后代数量的比值。
Fitness ranges from 0 (affected individuals never have children who survive to reproductive age) to 1 (affected individuals have the same number of offspring as unaffected controls).适合度范围从0（患病个体从未有存活至生育年龄的孩子）到1（患病个体的后代数量与未患病对照组相同）。
Although we will explore the impact of mutation, selection, and fitness on allele frequencies in greater detail in Chapter 10, here we discuss examples that illustrate the major concepts and range of impact of fitness on autosomal dominant conditions.尽管我们将在第10章更详细地探讨突变、选择和适合度对等位基因频率的影响，但在此我们讨论一些例子，以说明适合度对常染色体显性状况的主要影响概念和范围。
At one extreme are disorders that have a fitness of 0; patients with such disorders never reproduce, and the disorder is referred to as genetic lethal.一个极端是适合度为0的疾病；此类疾病患者从不生育，该疾病被称为遗传致死。
One example is the severe short-limb dwarfism syndrome known as thanatophoric dysplasia that occurs in heterozygotes for certain pathogenic alterations in the FGFR3 gene .一个例子是被称为致死性骨发育不全的严重短肢侏儒症综合征，发生于FGFR3基因特定致病性改变的杂合子中。
Thanatophoric dysplasia is lethal in the neonatal period, and therefore all probands with the disorder must be due to new mutations because these variants cannot be transmitted to the next generation.致死性骨发育不全在新生儿期致死，因此所有该病的先证者必定源于新生突变，因为这些变异无法传递给下一代。
At the other extreme are disorders that have virtually normal reproductive fitness because of a late age of onset or a mild phenotype that does not interfere with reproduction.另一个极端是那些由于发病年龄晚或表型轻微而不影响生殖，从而具有几乎正常生殖适合度的疾病。
If the fitness is normal, the disorder will only rarely be the result of new mutation; a patient is much more likely to have inherited the pathogenic variant, and the pedigree is likely to show multiple affected individuals with clear-cut autosomal dominant inheritance.如果适合度正常，该疾病很少是新突变的结果；患者更可能遗传了致病性变异，家系中可能显示多个患病个体，呈现明确的常染色体显性遗传。
Lateonset progressive hearing loss is a good example of such an autosomal dominant condition, with a fitness of ~1 .晚发性进行性听力丧失是此类常染色体显性状况的一个典型例子，其适合度约为1。
Thus, there is an inverse relation between the fitness of a given autosomal dominant disorder and the proportion of individuals with the disorder who inherited the defective gene, versus those who received it due to a new mutation.因此，给定常染色体显性疾病的适合度与遗传了缺陷基因的患者比例（相对于因新生突变而获得者）呈反比关系。
The measurement of mutation frequency and the relation of mutation frequency to fitness will be discussed further in Chapter 10.突变频率的测量以及突变频率与适合度的关系将在第10章进一步讨论。
It is important to note that fitness is not simply a measure of physical or intellectual disability.重要的是要注意，适合度并不仅仅是身体或智力残疾的衡量标准。
Some individuals with an autosomal dominant disorder may appear phenotypically normal but have a fitness of 0; at the other extreme, individuals may have normal or nearnormal fitness, despite being affected by an autosomal dominant condition with an obvious and severe phenotype, such as familial Alzheimer disease (Case 4).一些常染色体显性遗传病患者表型正常但适合度为0；而在另一个极端，患者尽管患有表型明显且严重的常染色体显性状况（如家族性阿尔茨海默病，病例4），却可能具有正常或接近正常的适合度。
X-LINKED INHERITANCE In contrast to genes on the autosomes, genes on the X and Y chromosomes are distributed unequally to males and females in families.X连锁遗传 与常染色体上的基因不同，X和Y染色体上的基因在家族中向男性和女性的分布是不均等的。
The patrilineal inheritance of the Y chromosome is straightforward.Y染色体的父系遗传简单明了。
However, there are very few strictly Y-linked genes, almost all of which are involved in primary sex determination or the development of secondary male characteristics, as discussed in Chapter 6, and they will not be considered here.然而，严格Y连锁的基因非常少，几乎全部涉及初级性别决定或男性第二性征的发育，如第6章所述，此处不再讨论。
Approximately 800 protein-coding and 300 noncoding RNA genes have been identified on the X chromosome to date, of which over 300 genes are presently known to be associated with X-linked disease phenotypes.迄今为止，X染色体上已鉴定出约800个蛋白质编码基因和300个非编码RNA基因，其中已知有300多个基因与X连锁疾病表型相关。
Phenotypes determined by genes on the X have a characteristic sex distribution and a pattern of inheritance that is usually easy to identify and easy to distinguish from the patterns of autosomal inheritance we just explored.由X染色体基因决定的表型具有特征性的性别分布和遗传模式，通常易于识别，也易于与我们刚探讨的常染色体遗传模式区分。
Because males have one X chromosome but females have two, there are only two possible genotypes in males and four in females with respect to pathogenic alleles at an X-linked locus.由于男性有一条X染色体而女性有两条，对于X连锁位点上的致病等位基因，男性只有两种可能的基因型，而女性有四种。
A male with a pathogenic allele at an X-linked locus is hemizygous for that allele, whereas females may be a homozygote for the wild-type allele, a homozygote for a pathogenic allele, a compound heterozygote for two different pathogenic alleles, or a heterozygous carrier of a pathogenic allele.在X连锁位点上携带致病等位基因的男性是该等位基因的半合子，而女性可以是野生型等位基因的纯合子、致病等位基因的纯合子、两种不同致病等位基因的复合杂合子，或致病等位基因的杂合携带者。
For example, if XH is the wild-type allele for an X-linked disease gene and Xh, is the disease allele, the genotypes expected in males and females are as in III II I P Reduced penetrance must be taken into account in genetic counseling.例如，如果XH是X连锁疾病基因的野生型等位基因，Xh是疾病等位基因，则男性和女性中预期的基因型如III II I P所示，在遗传咨询中必须考虑降低的外显率。
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X Inactivation, Dosage Compensation, and the Expression of X-Linked Genes As introduced in Chapters 3 and 6, X inactivat…
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X Inactivation, Dosage Compensation, and the Expression of X-Linked Genes As introduced in Chapters 3 and 6, X inactivation is a normal physiologic process in which most of the genes on one of the two X chromosomes in normal females, but not the genes on the single X chromosome in males, are inactivated in somatic cells, thus equalizing the expression of most X-linked genes between the two sexes.X失活、剂量补偿及X连锁基因的表达 如第3章和第6章所述，X失活是一种正常的生理过程，在该过程中，正常女性两条X染色体中一条上的大多数基因（而非男性单条X染色体上的基因）在体细胞中被失活，从而使两性之间大多数X连锁基因的表达达到平衡。
The clinical relevance of X inactivation in X-linked diseases is profound.X失活在X连锁疾病中的临床意义极为深远。
It leads to females having two cell populations, which express alleles of X-linked genes from one or the other of the two X chromosomes .它导致女性拥有两个细胞群体，这两个群体表达来自两条X染色体中任一条的X连锁基因的等位基因。
These two cell populations are thus genetically identical but functionally distinct, and both cell populations in human females can be readily detected for some disorders.因此，这两个细胞群体在遗传上相同但在功能上不同，并且在人类女性中，这两个细胞群体均可通过某些疾病被轻易检测到。
For example, in Duchenne muscular dystrophy (Case 14), female carriers exhibit typical mosaic expression of their dystrophin immunostaining .例如，在杜氏肌营养不良症（病例14）中，女性携带者表现出典型的抗肌萎缩蛋白免疫组化染色嵌合表达。
Depending on the pattern of random inactivation of the two X chromosomes, two female heterozygotes for an X-linked disease may have very different clinical presentations because they differ in the proportion of cells that have the pathogenic allele on the active X in a relevant tissue (as seen in manifesting heterozygotes, as described later).根据两条X染色体随机失活的模式，X连锁疾病的两位女性杂合子可能因相关组织中活性X染色体上携带致病等位基因的细胞比例不同而呈现截然不同的临床表现（如后文所述的表现性杂合子）。
Recessive and Dominant Inheritance of X-Linked Disorders As mentioned earlier in this chapter, the use of the terms dominant and recessive is different for X-linked conditions than for autosomal disorders.X连锁疾病的隐性和显性遗传 如本章前面所述，显性和隐性这两个术语在X连锁疾病中的使用与常染色体疾病不同。
So-called X-linked dominant and recessive patterns of inheritance are typically distinguished on the basis of the phenotype in heterozygous females.所谓的X连锁显性和隐性遗传模式通常根据杂合子女性的表型来区分。
Some X-linked phenotypes are consistently apparent clinically in carriers, at least to some degree; these are referred to as dominant.某些X连锁表型在携带者中至少在某种程度上持续临床可见；这些被称为显性。
Other X-linked phenotypes are typically not observed in heterozygous females and are considered to be recessive.其他X连锁表型通常在杂合子女性中不被观察到，被认为属于隐性。
The difficulty in classifying an X-linked disorder as dominant or recessive arises because females who are heterozygous for the same pathogenic allele in a family may or may not demonstrate the disease, depending on the pattern of random X inactivation and the proportion of the cells in pertinent tissues that have the pathogenic allele on the active or inactive X.将X连锁疾病分类为显性或隐性的困难在于，同一家族中相同致病等位基因的杂合子女性可能表现出也可能不表现出该疾病，这取决于随机X失活的模式以及相关组织中活性或失活X染色体上携带致病等位基因的细胞比例。
Nearly a third of X-linked disorders are penetrant in some (but not all) female heterozygotes and cannot be classified as either dominant or recessive.近三分之一的X连锁疾病在某些（而非全部）女性杂合子中具有外显性，无法被分类为显性或隐性。
Even for disorders that can be so classified, they show incomplete penetrance that varies as a function of X inactivation patterns, not inheritance patterns.即使对于可以如此分类的疾病，它们也表现出不完全外显率，其变化取决于X失活模式而非遗传模式。
Because clinical expression of an X-linked condition does not depend strictly on the particular gene involved, or even the particular A B C A normal female (×480).因为X连锁疾病的临床表达并不严格取决于所涉及的特定基因，甚至也不取决于特定的A B C A 正常女性（×480）。
(B) A male with Duchenne muscular dystrophy (DMD) (×480).(B) 患有杜氏肌营养不良症（DMD）的男性（×480）。
(C) A carrier female (×240).(C) 携带者女性（×240）。
Staining creates the bright signals seen here encircling individual muscle fibers.染色产生此处所见围绕单个肌纤维的明亮信号。
Muscle from DMD patients lacks dystrophin staining.DMD患者的肌肉缺乏抗肌萎缩蛋白染色。
Muscle from DMD carriers exhibits both positive and negative patches of dystrophin immunostaining, representing fibers with either the normal or pathogenic allele on the active X.DMD携带者的肌肉呈现抗肌萎缩蛋白免疫组化染色的阳性和阴性斑块，代表活性X染色体上具有正常或致病等位基因的肌纤维。
Images courtesy K.图像承蒙K.提供。
Arahata, National Institute of Neuroscience, Tokyo..Arahata，国立神经科学研究所，东京。
Genotypes and Phenotypes in X-Linked Disease Genotypes Phenotypes Males Hemizygous XH Unaffected Hemizygous Xh Affected Females Homozygous XH/XH Unaffected Heterozygous XH/Xh Carrier (may or may not be affected) Homozygous (or compound heterozygous) Xh/Xh AffectedX连锁疾病的基因型与表型 基因型 表型 男性 半合子XH 未患病 半合子Xh 患病 女性 纯合子XH/XH 未患病 杂合子XH/Xh 携带者（可能患病也可能不患病） 纯合子（或复合杂合子）Xh/Xh 患病
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Patterns of Single-Gene Inheritance 121 pathogenic variant in the same family, some geneticists have recommended dispens…
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Patterns of Single-Gene Inheritance 121 pathogenic variant in the same family, some geneticists have recommended dispensing altogether with the terms recessive and dominant for X-linked disorders.单基因遗传模式 121 同一家族中的致病性变异，一些遗传学家建议完全放弃对X连锁疾病使用隐性和显性术语。
Be that as it may, the terms are widely applied to X-linked disorders, and we will continue to use them, recognizing that they describe extremes of a continuum of penetrance and expressivity in female carriers of X-linked diseases.尽管如此，这些术语仍被广泛用于X连锁疾病，我们将继续使用它们，同时认识到它们描述了X连锁疾病女性携带者中外显率和表现度连续谱的两个极端。
X-Linked Recessive Inheritance The inheritance of X-linked recessive phenotypes follows a well-defined and easily recognized pattern .X连锁隐性遗传 X连锁隐性表型的遗传遵循一个明确且易于识别的模式。
An X-linked recessive trait is expressed phenotypically in all males who receive the variant allele, and, consequently, X-linked recessive disorders are generally restricted to males.X连锁隐性性状在所有携带变异等位基因的男性中表型表达，因此，X连锁隐性疾病通常仅限于男性。
Hemophilia A is a classic X-linked recessive disorder in which the blood fails to clot normally because of a deficiency of factor VIII, a protein in the clotting cascade (Case 21).血友病A
The hereditary nature of hemophilia and even its pattern of transmission have been recognized since ancient times, and the condition became known as the “royal hemophilia” because of its occurrence among descendants of Britain’s Queen Victoria, who was a carrier.[TL:missing]
As in the earlier discussion, suppose Xh represents a pathogenic allele of factor VIII causing hemophilia A, and XH represents the normal allele.[TL:missing]
The sons of a male with hemophilia and a noncarrier female receive their I II III IV 3 3 5 2 2 CHARACTERISTICS OF X-LINKED RECESSIVE INHERITANCE The incidence of the trait is much higher in males than in females.[TL:missing]
Heterozygous females are usually unaffected, but some may express the condition with variable severity as determined by the pattern of X inactivation.[TL:missing]
The gene responsible for the condition is transmitted from an affected man through all his daughters.[TL:missing]
Any of his daughters’ sons has a 50% chance of inheriting it.[TL:missing]
The pathogenic allele is never transmitted directly from father to son, but it is transmitted by an affected male to all his daughters.[TL:missing]
The pathogenic allele may be transmitted for many generations through a series of carrier females; if so, the affected males in a kindred are related through females.[TL:missing]
A significant proportion of isolated cases are due to new mutation. father’s Y chromosome and a maternal X and are unaffected, but the daughters receive the paternal X chromosome with its hemophilia allele and are obligate carriers.[TL:missing]
Children of obligate carrier females have four possible genotypes, with equal probabilities ( The hemophilia of an affected grandfather, which did not appear in any of his own children, has a 50% chance of appearing in each son of his daughters.[TL:missing]
It will not reappear among the descendants of his sons, however.[TL:missing]
A daughter of a carrier has a 50% chance of being a carrier herself .[TL:missing]
By chance, an X-linked recessive allele may be transmitted undetected through a series of female carriers before it is expressed in a male descendant.[TL:missing]
Affected Females in X-Linked Recessive Disease Although X-linked conditions are classically seen only in males, they can be observed in females under two circumstances.[TL:missing]
In one, a female can be homozygous for the relevant disease allele.[TL:missing]
This scenario is unlikely unless her parents are consanguineous; additionally the phenotype can not have a reproductive fitness of 0 in males.[TL:missing]
However, a few X-linked conditions, such as X-linked color blindness, are sufficiently common and mild that such homozygotes are seen in female offspring of an affected father and a carrier mother.[TL:missing]
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More commonly, a female carrier of an X-linked allele who has phenotypic expression of the disease is referred to as a m…
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More commonly, a female carrier of an X-linked allele who has phenotypic expression of the disease is referred to as a manifesting heterozygote.更常见的是，具有疾病表型表现的X连锁等位基因女性携带者被称为表现杂合子。
Whether a female carrier will be a manifesting heterozygote depends on a number of features of X inactivation.女性携带者是否会成为表现杂合子取决于X失活的若干特征。
First, as we saw in Chapter 3, the choice of which X chromosome is to become inactive is random, but it occurs when there is a relatively small number of cells in the developing female embryo.首先，如第三章所见，哪条X染色体失活的选择是随机的，但这发生在发育中的女性胚胎细胞数量相对较少时。
By chance alone, therefore, the fraction of cells in various tissues of carrier females in which the normal or pathogenic allele happens to remain active may deviate substantially from the expected 50%, resulting in unbalanced or skewed X inactivation .因此，仅凭随机性，携带者女性不同组织中正常或致病等位基因恰好保持活性的细胞比例可能显著偏离预期的50%，导致不平衡或偏斜的X失活。
A female carrier may have signs and symptoms of an X-linked disorder if the skewed inactivation is unfavorable (i. e., a large majority of the active X chromosomes in pertinent tissues happen to contain the deleterious allele active).如果偏斜失活是不利的（即相关组织中绝大多数活性X染色体恰好含有有害等位基因并保持活性），女性携带者可能出现X连锁疾病的体征和症状。
Favorably unbalanced or skewed inactivation also occurs, in which the pathogenic allele is preferentially on the inactive X in some or all tissues of an unaffected heterozygous female.有利的不平衡或偏斜失活也会发生，即未受累杂合女性的部分或全部组织中致病等位基因优先位于失活X染色体上。
Such skewed inactivation may simply be due to chance alone, as we just saw (albeit in the opposite direction).这种偏斜失活可能仅仅源于随机性，正如我们刚才所见（尽管方向相反）。
However, in certain X-linked conditions, there is reduced cell survival (or a proliferative disadvantage) for those cells that originally had the pathogenic allele on the active X early in development.然而，在某些X连锁疾病中，那些在发育早期活性X染色体上原本携带致病等位基因的细胞存活率降低（或存在增殖劣势）。
This results in a pattern of highly skewed inactivation that favors cells with the normal allele on the active X in relevant ­tissues.这导致一种高度偏斜失活的模式，有利于相关组织中活性X染色体携带正常等位基因的细胞。
For example, highly skewed X inactivation is the rule in female carriers of certain X-linked immunodeficiencies, in whom only those early progenitor cells that happen to carry the normal allele on their active X chromosome can populate certain lineages in the immune system.例如，在某些X连锁免疫缺陷的女性携带者中，高度偏斜的X失活是常态，在这些女性中，只有那些活性X染色体上恰好携带正常等位基因的早期祖细胞才能在免疫系统的某些谱系中定居。
X-Linked Dominant Inheritance As discussed earlier, an X-linked phenotype can be described as dominant if it is regularly expressed in heterozygotes.X连锁显性遗传 如前所述，如果一种X连锁表型在杂合子中规律表达，则可将其描述为显性。
X-linked dominant inheritance (6 X-Linked Dominant Inheritance Unaffected Male and Affected Female Female Genotype XD/Xd Gametes Risk for Disease XD Xd Male Genotype Xd/Y Gametes Xd XD/Xd Xd/Xd ¼ Affected females (XD/Xd) ¼ Unaffected females (Xd/Xd) ¼ Affected males (XD/Y) ¼ Unaffected males (Xd/Y) Y XD/Y Xd/Y Affected Male and Affected Female Female Genotype Xd/Xd Gametes Risk for Disease Xd Xd Male Genotype XD/Y Gametes XD XD/Xd XD/Xd All females affected (XD/Xd) All males unaffected (Xd/Y) Y Xd/Y Xd/Y The wild-type allele at the hypophosphatemic rickets locus is denoted as Xd, and the pathogenic allele is denoted as XD. impossible for X-linked inheritance because males transmit the Y chromosome, not the X, to their sons.X连锁显性遗传（6 X连锁显性遗传 未受累男性与受累女性 女性基因型 XD/Xd 配子 疾病风险 XD Xd 男性基因型 Xd/Y 配子 Xd XD/Xd Xd/Xd ¼ 受累女性 (XD/Xd) ¼ 未受累女性 (Xd/Xd) ¼ 受累男性 (XD/Y) ¼ 未受累男性 (Xd/Y) Y XD/Y Xd/Y 受累男性与受累女性 女性基因型 Xd/Xd 配子 疾病风险 Xd Xd 男性基因型 XD/Y 配子 XD XD/Xd XD/Xd 所有女性受累 (XD/Xd) 所有男性未受累 (Xd/Y) Y Xd/Y Xd/Y 低磷血症性佝偻病位点的野生型等位基因记为Xd，致病等位基因记为XD。这对于X连锁遗传是不可能的，因为男性将Y染色体而非X染色体传给其儿子。
Thus the distinguishing feature of a fully penetrant X-linked dominant pedigree is that all the daughters and none of the sons of affected males are affected; if any daughter is unaffected or any son is affected, the inheritance must be autosomal, not X linked.因此，完全外显的X连锁显性遗传系谱的显著特征是受累男性的所有女儿均受累，而儿子均不受累；如果有任何女儿未受累或任何儿子受累，则遗传方式必须是常染色体遗传，而非X连锁遗传。
The pattern of inheritance through females is no different from the autosomal dominant pattern; because females have a pair of X chromosomes just as they have pairs of autosomes, each child of an affected female has a 50% chance of inheriting the trait, regardless of sex.通过女性传递的遗传模式与常染色体显性遗传模式无差别；因为女性拥有一对X染色体，正如她们拥有一对常染色体，受累女性的每个子女无论性别均有50%的概率继承该性状。
Across multiple families with an X-linked dominant disease, the expression is usually milder in heterozygous females because the pathogenic allele is located on the inactive X chromosome in a proportion of their cells.在多个患有X连锁显性疾病的家族中，杂合女性的表现通常较轻，因为其部分细胞中致病等位基因位于失活X染色体上。
Thus, most X-linked dominant disorders are incompletely dominant, as is the case with most autosomal dominant disorders (3)..因此，大多数X连锁显性疾病为不完全显性，正如大多数常染色体显性疾病（3）那样。
CHARACTERISTICS OF X-LINKED DOMINANT INHERITANCE Affected males with unaffected partners have no affected sons and no unaffected daughters.X连锁显性遗传的特征 受累男性与未受累伴侣所生后代中，无受累儿子，也无未受累女儿。
Both male and female offspring of female carriers have a 50% risk for inheriting the phenotype.女性携带者的男性后代和女性后代均有50%的风险继承该表型。
The pedigree pattern is similar to that seen with autosomal dominant inheritance.系谱模式与常染色体显性遗传见到的相似。
Affected females are approximately twice as common as affected males, but affected females typically have milder (although variable) expression of the phenotype.受累女性大约是受累男性的两倍常见，但受累女性通常具有较温和（尽管可变）的表型表现。
One example of an X-linked dominant disorder is X-linked hypophosphatemic rickets (also known as vitamin D–resistant rickets), in which the ability of the kidney tubules to reabsorb filtered phosphate is impaired.X连锁显性疾病的一个例子是X连锁低磷血症性佝偻病（也称为维生素D抵抗性佝偻病），其中肾小管重吸收滤过磷酸盐的能力受损。
This disorder fits the criterion of an X-linked dominant disorder in that both sexes are affected, although the serum phosphate level is less depressed and the rickets less severe in heterozygous females than in affected males.该疾病符合X连锁显性疾病的标準，即两性均受累，尽管杂合女性的血清磷酸盐水平降低较轻，佝偻病较受累男性轻。
X-Linked Dominant Disorders With Male Lethality Although most X-linked conditions are typically apparent only in males, a few rare X-linked defects are expressed exclusively, or almost exclusively, in females.伴男性致死的X连锁显性疾病 尽管大多数X连锁疾病通常仅见于男性，但少数罕见的X连锁缺陷仅（或几乎仅）在女性中表达。
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Patterns of Single-Gene Inheritance 123 I II III IV I II III the same families are completely unaffected .
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Patterns of Single-Gene Inheritance 123 I II III IV I II III the same families are completely unaffected .单基因遗传模式 123 I II III IV I II III 同一家族完全不受影响。
The disorder is due to loss-of-function variants in the protocadherin gene 19, an X-linked gene that encodes a cell surface molecule expressed on neurons in the central nervous system.该疾病是由于原钙黏蛋白19基因的功能缺失变异引起的，该基因是X连锁基因，编码一种在中枢神经系统神经元上表达的细胞表面分子。
The explanation for this unusual pattern of inheritance is not clear.这种不寻常遗传模式的解释尚不明确。
It is hypothesized that the epilepsy occurs in females because mosaicism for expression of protocadherin 19, resulting from random X inactivation in the brain, disrupts communication between groups of neurons with and without the cell surface protein.假设女性发生癫痫是因为原钙黏蛋白19表达的嵌合现象（由大脑中随机X失活导致）破坏了带有和不带有该细胞表面蛋白的神经元群之间的通信。
Neurons in males uniformly lack the cell surface molecule, but their brains are apparently spared cell-cell miscommunication by a different, compensating protocadherin.男性的神经元统一缺乏该细胞表面分子，但他们的大脑显然通过另一种不同的、补偿性的原钙黏蛋白避免了细胞间通信错误。
Relationship Between New Mutation and Fitness in X-Linked Disorders Just as with autosomal dominant disorders, new mutations account for a significant fraction of isolated cases of many X-linked diseases.X连锁疾病中新突变与适应度之间的关系 与常染色体显性遗传病一样，新突变占许多X连锁疾病散发病例的很大一部分。
Males carrying variants causing X-linked disorders are exposed to selection that is complete for some disorders, partial for others, and absent for still others, depending on the fitness of the genotype.携带导致X连锁疾病变异的男性会受到选择，这种选择对某些疾病是完全的，对另一些是部分的，对还有一些则不存在，取决于基因型的适应度。
Males carrying pathogenic alleles for X-linked disorders such as Duchenne muscular dystrophy (Case 14)—a disease of muscle that affects young boys, do not reproduce.携带X连锁疾病（如杜氏肌营养不良症，病例14——一种影响年轻男孩的肌肉疾病）致病等位基因的男性不进行繁殖。
Fitness of affected males is currently 0, although the situation I II III 1 2 3 4 5 6 7 8 9 10 11 1 2 1 2 3 4 5 6 7 8 9 10 These X-linked dominant conditions are lethal in males before birth .患病男性的适应度目前为0，尽管情况 I II III 1 2 3 4 5 6 7 8 9 10 11 1 2 1 2 3 4 5 6 7 8 9 10 这些X连锁显性遗传病在男性出生前即致死。
Typical pedigrees of these conditions show transmission by affected females, who produce affected daughters, normal daughters, and normal sons in equal proportions (1:1:1); affected liveborn males are not seen.这些疾病的典型家系显示由患病女性传递，她们产生患病女儿、正常女儿和正常儿子的比例相等（1:1:1）；未见患病的活产男性。
Rett syndrome (Case 40) is a striking disorder that occurs nearly exclusively in females and meets all criteria for being an X-linked dominant disorder that is usually lethal in hemizygous males.雷特综合征（病例40）是一种引人注目的疾病，几乎仅发生于女性，并且满足作为X连锁显性遗传病（通常在半合子男性中致死）的所有标准。
The syndrome is characterized by normal prenatal and neonatal growth and development, followed by the rapid onset of neurologic symptoms in affected girls.该综合征的特征是正常出生前及新生儿期的生长和发育，随后在患病女孩中快速出现神经系统症状。
The disease mechanism is thought to reflect abnormalities in the regulation of a set of genes in the developing brain; the cause of male lethality is unknown but presumably reflects a requirement during early development for at least one functional copy of the MECP2 gene on the X chromosome.该疾病的机制被认为反映了发育中大脑内一组基因调控的异常；男性致死的原因尚不清楚，但推测反映了早期发育过程中X染色体上至少需要一个功能性MECP2基因拷贝的需求。
X-Linked Dominant Disorders With Male Sparing Other disorders are manifest only in carrier females because hemizygous males are largely spared the consequences of the variant they carry.X连锁显性遗传病伴男性豁免 其他疾病仅出现于携带者女性，因为半合子男性在很大程度上免于其所携带变异的影响。
One such disorder is female-limited, X-linked epilepsy and cognitive impairment.其中一种疾病是女性局限性的X连锁癫痫和认知障碍。
Affected females are asymptomatic at birth and appear to be developing normally but begin to have seizures, generally in the second year of life, after which development begins to regress.患病女性出生时无症状，发育看似正常，但通常在出生后第二年开始出现癫痫发作，此后发育开始退化。
Most affected females go on to be developmentally delayed, which can vary from mild to severe.大多数患病女性随后出现发育迟缓，程度可从轻度到重度不等。
In contrast, male hemizygotes in相比之下，男性半合子在
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may change as a result of advances in research aimed at therapy for affected boys (see Chapter 14).
Ch7 — Segment 16
may change as a result of advances in research aimed at therapy for affected boys (see Chapter 14).可能因针对患病男孩治疗研究的进展而改变（见第14章）。
In contrast, individuals with hemophilia (Case 21) also have reduced fitness, but the condition is not a genetic lethal.相比之下，血友病（病例21）患者的适应度也降低，但该病并非遗传致死性疾病。
Affected males have, on average, ~70% as many offspring as unaffected males do, and fitness of affected males is therefore ~0. 70.患病男性平均拥有的后代数量约为未患病男性的70%，因此患病男性的适应度约为0.70。
This fitness may also increase with improvements in the treatment of this disease.这种适应度也可能随着该疾病治疗方法的改进而提高。
When fitness is reduced, the pathogenic alleles that these males carry are lost from the population.当适应度降低时，这些男性携带的致病等位基因会从群体中消失。
In contrast to autosomal dominant conditions, however, pathogenic alleles for X-linked diseases with reduced fitness may be partially or completely protected from selection when present in females.然而，与常染色体显性遗传病不同，对于适应度降低的X连锁遗传病，致病等位基因在女性中可能部分或完全免受选择压力。
Thus, even in X-linked disorders with a fitness of 0, less than half of new cases will be due to new mutations.因此，即使在适应度为0的X连锁遗传病中，新发病例中不到一半是由新发突变引起的。
The overall incidence of the disease, then, will be determined both by the transmittal of a pathogenic allele from a carrier mother and by the rate of de novo mutations at the responsible locus.因此，该疾病的总体发病率将由携带者母亲传递致病等位基因和致病位点的新发突变率共同决定。
The balance between new mutation and selection will be discussed more fully from the population genetics perspective in Chapter 10.新发突变与选择之间的平衡将在第10章从群体遗传学角度进行更全面的讨论。
PSEUDOAUTOSOMAL INHERITANCE As we first saw in Chapter 2, meiotic recombination between X-linked loci only occurs between the two homologous X chromosomes and is, therefore, restricted to females.假常染色体遗传 正如我们在第2章首次见到的，X连锁位点之间的减数分裂重组仅发生在两条同源X染色体之间，因此仅限于女性。
X-linked loci do not participate in meiotic recombination in males, who have a Y chromosome and only one X chromosome.X连锁位点不参与男性的减数分裂重组，因为男性拥有一条Y染色体和仅一条X染色体。
There are, however, a small number of contiguous loci, located at the tips of the p and q arms of the sex chromosomes, that are homologous between X and Y and recombine in male meiosis.然而，存在少量连续位点，位于性染色体的p臂和q臂末端，这些位点在X和Y之间同源，并在男性减数分裂中发生重组。
As a consequence, during spermatogenesis, a pathogenic allele at one of these loci on the X chromosome can be transferred onto the Y chromosome and passed on to male offspring, thereby demonstrating the male-to-male transmission characteristic of autosomal inheritance.因此，在精子发生过程中，X染色体上这些位点之一的致病等位基因可以转移到Y染色体上，并传递给男性后代，从而表现出常染色体遗传的男性向男性传递特征。
Because these unusual loci on the X and Y mimic autosomal inheritance but are not located on an autosome, they are referred to as pseudoautosomal loci; the segments of the X and Y chromosomes where they are located are referred to as the pseudoautosomal regions.由于X和Y上的这些特殊位点模拟常染色体遗传但并非位于常染色体上，因此被称为假常染色体位点；它们所在的X和Y染色体片段被称为假常染色体区。
One example of a disease caused by a pathogenic variant at a pseudoautosomal locus is dyschondrosteosis, a dominantly inherited skeletal dysplasia with disproportionate short stature and deformity of the forearms.由假常染色体位点致病性变异引起的一种疾病是软骨发育不良（dyschondrosteosis），这是一种常染色体显性遗传的骨骼发育不良，表现为不成比例的身材矮小和前臂畸形。
Although a greater prevalence in females than in males initially suggested an X-linked dominant disorder, the presence of male-to-male transmission clearly ruled out strict X-linked inheritance .尽管女性患病率高于男性最初提示为X连锁显性遗传病，但男性向男性传递的存在明确排除了严格的X连锁遗传。
Variants in the SHOX or SHOXY gene, located in the pseudoautosomal region on Xp and Yp, respectively, are responsible for this condition.位于Xp和Yp假常染色体区的SHOX或SHOXY基因变异导致了该疾病。
MOSAICISM Although we are used to thinking of ourselves as being composed of cells that all carry the same complement of genes and chromosomes, this is in reality an oversimplified view.嵌合体 尽管我们习惯于认为自身由携带相同基因和染色体组成的细胞构成，但这实际上是一种过于简化的观点。
Mosaicism is the presence in an individual or a tissue of at least two cell lineages that differ genetically but are derived from a single zygote.嵌合体是指个体或组织中存在至少两种遗传上不同但来源于同一受精卵的细胞系。
Mutations that occur after conception in a single cell in either prenatal or postnatal life can give rise to clones of cells genetically different from the original zygote because, given the nature of DNA replication, the altered allele will persist in all the clonal descendants of that cell .受孕后发生在单个细胞中的突变，无论是在产前还是产后，都可以产生遗传上不同于原始受精卵的细胞克隆，因为由于DNA复制的性质，改变的等位基因将存在于该细胞的所有克隆后代中。
Mosaicism for numeric or structural abnormalities of chromosomes is a clinically important phenomenon (see Chapters 5 and 17), and somatic mutation is recognized as the major contributor to most types of cancer (see Chapter 16).染色体数目或结构异常的嵌合体是一种临床上重要的现象（见第5章和第17章），体细胞突变被认为是大多数类型癌症的主要成因（见第16章）。
Mosaicism can affect any cells or tissue within a developing embryo or at any point from after conception to adulthood.嵌合体可影响发育中胚胎内的任何细胞或组织，或从受孕后到成年期的任何时间点。
It can be a diagnostic dilemma to determine just how widespread the mosaic pattern is.确定嵌合模式究竟有多广泛可能是一个诊断难题。
For example, the population of cells that carry a mutation in a mosaic pregnancy might be (a) found only in extraembryonic tissue and not in the embryo proper (confined placental mosaicism, see Chapter 18), (b) present in some tissues of the embryo but not in the gametes (pure somatic mosaicism), (c) restricted to the gamete lineage only and nowhere else (pure germline mosaicism), or (d) present in both somatic lineages and the germline.例如，在嵌合妊娠中携带突变的细胞群体可能（a）仅存在于胚胎外组织而胚胎本身没有（局限性胎盘嵌合体，见第18章），（b）存在于胚胎的某些组织但不在生殖细胞中（纯体细胞嵌合体），（c）仅限于生殖细胞系而不在其他部位（纯生殖系嵌合体），或（d）同时存在于体细胞系和生殖系中。
This all depends on whether the mutation occurred before or after the separation of the inner cell mass, the germline cells, and the somatic cells during embryogenesis (see Chapter 18).这一切取决于突变发生于胚胎发生过程中内细胞团、生殖系细胞和体细胞分离之前还是之后（见第18章）。
Because there are ~30 mitotic divisions in the cells of the germline before meiosis in the female and several hundred in the male (see Chapter 2), there is ample opportunity for mutation to occur in germline I II III IV The arrow shows a male who inherited the trait on his Y chromosome from his father.由于女性生殖系细胞在减数分裂前约有30次有丝分裂，男性则有数百次（见第2章），因此生殖系中发生突变的机会很大，I II III IV 箭头显示一名男性从其父亲处遗传了Y染色体上的性状。
His father, however, inherited the trait on his X chromosome from his mother.然而，他的父亲是从
From Shears DJ, Vassal HJ, Goodman FR, et al: Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis, Nat Genet 19:70–73, 1998.[TL:missing]
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Patterns of Single-Gene Inheritance 125 cells after the separation from somatic cells, resulting in pure gonadal mosaici…
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Patterns of Single-Gene Inheritance 125 cells after the separation from somatic cells, resulting in pure gonadal mosaicism.单基因遗传模式：125个细胞在从体细胞分离后，导致纯性腺嵌合体。
Determining whether mosaicism for a mutation is present only in the germline or only in somatic tissues may be difficult.确定突变的嵌合体是仅存在于种系中还是仅存在于体细胞组织中可能很困难。
Failure to find evidence in a subset of cells from a readily accessible somatic tissue (e. g., peripheral white blood cells, skin, or buccal cells) does not ensure that the mutation is not present elsewhere in the body, including the germline.在易于获取的体细胞组织（例如外周白细胞、皮肤或口腔黏膜细胞）的一部分细胞中未能找到证据，并不能保证该突变不存在于身体其他部位，包括种系中。
Segmental Mosaicism A mutation affecting morphogenesis and occurring during embryonic development might be manifested as a segmental or patchy abnormality, depending on the stage at which the mutation occurred and the lineage of the somatic cell in which it originated.节段性嵌合体：影响形态发生且发生在胚胎发育期间的突变可能表现为节段性或斑片状异常，具体取决于突变发生的阶段以及起源的体细胞谱系。
For example, NF1 (Case 34) is sometimes segmental, affecting only one part of the body.例如，NF1（病例34）有时是节段性的，仅影响身体的一部分。
Segmental NF1 is caused by somatic mosaicism for the outcome of a mutation that occurred after conception.节段性NF1是由受孕后发生的突变导致的体细胞嵌合体引起的。
Although the parents of such an individual would be unaffected and considered not at risk for transmitting the mutated allele, a patient with segmental NF1 could be at risk for having an affected child, whose phenotype would be typical for NF1; that is, not segmental.尽管此类个体的父母不会受影响，且被认为没有传播突变等位基因的风险，但节段性NF1患者可能有生育患病子女的风险，其子女的表型将表现为典型的NF1，即非节段性。
Whether the individual is at risk for transmitting the defect will depend on whether the mutation occurred before separation of germline cells from the somatic cell line.个体是否存在传播缺陷的风险取决于突变发生在种系细胞与体细胞系分离之前还是之后。
Germline Mosaicism In pedigrees with germline mosaicism, unaffected individuals with no evidence of a given disease-causing mutation in their genome (as evidenced by the failure to find an altered allele the mutation in DNA extracted from their peripheral white blood cells) may still be at risk for having more than one child who inherited the mutation from them .种系嵌合体：在有种系嵌合体的家系中，未受影响的个体在其基因组中没有特定致病突变的证据（如从其外周白细胞提取的DNA中未能发现改变的等位基因突变所证明），但仍可能有风险生育一个以上从其遗传了该突变的孩子。
The existence of germline mosaicism means that geneticists and genetic counselors must be aware that normal examination results and normal gene test results of the parents of a child with an autosomal dominant or X-linked phenotype do not necessarily mean there is no risk of recurrence.种系嵌合体的存在意味着遗传学家和遗传咨询师必须意识到，常染色体显性或X连锁表型患儿的父母，其正常的检查结果和正常的基因检测结果并不一定意味着没有复发风险。
The impact of this possibility on risk assessment will be discussed further in Chapter 17.这种可能性对风险评估的影响将在第17章进一步讨论。
Mutation Mutated cells Such a mutation can lead to a proportion of cells carrying the mutation – that is, to either somatic or germline mosaicism, depending on the stage of embryonic or postnatal development where the mutation occurred.突变 突变细胞 这样的突变可导致一定比例的细胞携带该突变，即导致体细胞或种系嵌合体，具体取决于突变发生的胚胎或出生后发育阶段。
No pathogenic variant FBN1 variant Arg 1137Pro No pathogenic variant DMD variant Ala 68Asp A B In family A, the affected children have the same single nucleotide variant inherited from their father, who is unaffected and does not carry the variant in DNA from examined somatic tissues.无致病性变异 FBN1变异Arg1137Pro 无致病性变异 DMD变异Ala68Asp A B 在家族A中，患病儿童具有相同的单核苷酸变异，从他们的父亲遗传而来，父亲未受影响，并且在所检查的体细胞组织DNA中不携带该变异。
He must have been a mosaic for the FBN1 variant in his germline.他必定是其种系中FBN1变异的嵌合体。
In family B, the affected children have the same single nucleotide variant inherited from their mother who is unaffected and does not carry the variant in DNA from examined somatic tissues.在家族B中，患病儿童具有相同的单核苷酸变异，从他们的母亲遗传而来，母亲未受影响，并且在所检查的体细胞组织DNA中不携带该变异。
She must have been a mosaic for the DMD variant in her germline.她必定是其种系中DMD变异的嵌合体。
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PARENT-OF-ORIGIN EFFECTS ON INHERITANCE PATTERNS Unusual Inheritance Patterns due to Genomic Imprinting According to Men…
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PARENT-OF-ORIGIN EFFECTS ON INHERITANCE PATTERNS Unusual Inheritance Patterns due to Genomic Imprinting According to Mendel’s laws of heredity, a pathogenic allele of an autosomal gene is equally likely to be transmitted from a parent of either sex to an offspring of either sex; similarly, a female is equally likely to transmit a variant X-linked allele to a child of either sex.亲本来源效应对遗传模式的影响：由基因组印记导致的异常遗传模式。根据孟德尔遗传定律，常染色体基因的致病等位基因从任一性别的亲本传递给任一性别子代的可能性相同；同样，女性将变异X连锁等位基因传递给任一性别子代的可能性也相同。
Originally, little attention was paid to whether the sex of the parent had any effect on the expression of the genes each parent transmits.最初，很少有人关注亲本的性别对其所传递基因的表达是否具有影响。
As discussed in Chapter 6, we now know that in some genetic disorders, such as Prader-Willi syndrome (Case 38) and Angelman syndrome, expression of the disease phenotype depends on whether the pathogenic allele has been inherited from the father or from the mother.如第6章所述，我们现在知道，在一些遗传性疾病中，例如普拉德-威利综合征（病例38）和安格尔曼综合征，疾病表型的表达取决于致病等位基因是遗传自父亲还是母亲。
This phenomenon is known as genomic imprinting.这种现象被称为基因组印记。
The hallmark of genomic imprinting is that the sex of the parent who transmits the pathogenic allele determines whether there is expression of the disorder in a child (see Chapter 8).基因组印记的标志是，传递致病等位基因的亲本的性别决定了该疾病是否在子代中表达（见第8章）。
This is very different from sex-limited inheritance (described earlier in this chapter), in which expression of the disease depends on the sex of the child who inherits the pathogenic allele.这与性别限制性遗传（本章前面已描述）非常不同，后者中疾病的表达取决于继承致病等位基因的子代的性别。
Imprinting can cause unusual inheritance patterns: a disorder can appear to be inherited in a dominant manner when transmitted from one parent, but not from the other.印记可导致异常遗传模式：一种疾病在从某一亲本传递时可能表现为显性遗传，但从另一亲本传递时则不然。
For example, the hereditary paragangliomas (PGLs) are a group of autosomal dominant disorders in which multiple tumors develop in sympathetic and parasympathetic ganglia of the autonomic nervous system.例如，遗传性副神经节瘤（PGLs）是一组常染色体显性遗传疾病，其特征是在自主神经系统的交感神经节和副交感神经节中形成多个肿瘤。
Individuals with paraganglioma can also develop a catecholamine-producing tumor known as a pheochromocytoma, either in the adrenal medulla or in sympathetic ganglia along the vertebral column.患有副神经节瘤的个体也可能发展出一种产生儿茶酚胺的肿瘤，称为嗜铬细胞瘤，可发生于肾上腺髓质或沿脊柱的交感神经节中。
A pedigree of one type of PGL family, caused by a pathogenic variant in the SDHD gene, is shown in .由SDHD基因致病性变异引起的一种PGL家族的家系图如所示。
These conditions are characterized by an unstable expansion within the affected gene of a segment of DNA that consists of tandem repeating units of three or more nucleotides.这些疾病的特征是在受累基因内有一段由三个或更多核苷酸串联重复单元组成的DNA片段发生不稳定性扩增。
Many such repeat units consist of three nucleotides, such as CAG or CCG; the repeat being CAGCAGCAGCAG... or CCGCCGCCGCCG, for example.许多此类重复单元由三个核苷酸组成，例如CAG或CCG；例如，重复序列为CAGCAGCAGCAG...或CCGCCGCCGCCG。
In general, gene loci associated with these diseases are polymorphic; that is, alleles in the normal population have a variable number of repeat units, as we saw in Chapter 4.通常，与这些疾病相关的基因位点是多态的；也就是说，正常群体中的等位基因具有可变数量的重复单元，正如我们在第4章所见。
As the gene is passed from generation to generation, the number of repeats can increase and undergo expansion, far beyond the normal range, leading to abnormalities in gene expression and function.随着基因代代相传，重复次数可以增加并发生扩增，远超正常范围，导致基因表达和功能异常。
I II III IV 1 2 3 4 5 6 7 8 9 10 17 16 15 14 13 12 11 18 + + + + + + + + + + 1 2 3 4 5 6 7 8 9 10 1 2 1 2 3 4 + + + + + + + + + + Individuals II-1, II-2, II-4, III2, III-3, III-9, III-10, IV-6, IV-7, IV-11, and IV-14 each inherited the variant from their mothers but are unaffected.I II III IV 1 2 3 4 5 6 7 8 9 10 17 16 15 14 13 12 11 18 + + + + + + + + + + 1 2 3 4 5 6 7 8 9 10 1 2 1 2 3 4 + + + + + + + + + + 个体II-1、II-2、II-4、III-2、III-3、III-9、III-10、IV-6、IV-7、IV-11和IV-14各自从母亲那里遗传了变异，但未患病。
However, when the males in this group pass on the variant, those children can be affected.然而，当这一群体中的男性传递该变异时，他们的子代可能会患病。
In addition to the imprinting, the family demonstrates the effect of reduced and age-dependent penetrance in the children (III-6, IV-10, IV-17) of heterozygous fathers.除了印记之外，该家系还显示了杂合父亲所生子女（III-6、IV-10、IV-17）中降低且年龄依赖的外显率效应。
The + and − symbols refer to the presence or absence of the SDHD variant in this family.+和−符号表示该家系中SDHD变异的存在或缺失。
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Patterns of Single-Gene Inheritance 127 The discovery of this unusual group of conditions has dispelled the orthodox not…
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Patterns of Single-Gene Inheritance 127 The discovery of this unusual group of conditions has dispelled the orthodox notions of germline stability and provided a biologic basis for peculiarities of familial transmission (discussed in the next section) that previously had no known mechanistic explanation.单基因遗传模式 127 这一不寻常疾病群的发现，打破了关于种系稳定性的正统观念，并为家族遗传的异常现象（在下一节讨论）提供了生物学基础，这些现象此前没有任何已知的机制解释。
More than 70 diseases are known to result from unstable repeat expansions of this type.已知超过70种疾病是由这种类型的不稳定重复扩增引起的。
All of these conditions are primarily neurologic.所有这些疾病主要都是神经系统的。
Here, we will review the inheritance patterns of two different diseases that illustrate the effects that different dynamic mutations can have on patterns of inheritance.在此，我们将回顾两种不同疾病的遗传模式，它们说明了不同的动态突变对遗传模式可能产生的影响。
A more complete description of the pathogenic mechanisms of unstable repeat disorders is given in Chapter 13.关于不稳定重复疾病致病机制的更完整描述见第13章。
Polyglutamine Disorders Several different neurologic diseases share the property that the protein encoded by the implicated gene has a variable-length string of consecutive glutamine residues, which can be encoded by the trinucleotide CAG.多聚谷氨酰胺疾病 几种不同的神经系统疾病具有共同特性：由相关基因编码的蛋白质含有一串长度可变的连续谷氨酰胺残基，这些残基可由三核苷酸CAG编码。
These so-called polyglutamine disorders result when an expansion of the CAG repeat leads to a protein with more glutamines than is compatible with normal function.这些所谓多聚谷氨酰胺疾病，是由于CAG重复扩增导致蛋白质中谷氨酰胺数量超过正常功能所允许的范围而发生的。
Huntington disease (HD) is a well-known disorder that illustrates many of the common genetic features of such disorders (Case 24).亨廷顿病（HD）是一种众所周知的疾病，它展示了此类疾病的许多常见遗传特征（病例24）。
The neuropathology is dominated by degeneration of the striatum and the cortex.神经病理学上以纹状体和皮质变性为主。
Individuals first present clinically in midlife, manifesting a characteristic phenotype of motor abnormalities (chorea, dystonia), personality changes, a gradual loss of cognition, and ultimately death.患者通常在中年首次出现临床症状，表现出特征性表型：运动异常（舞蹈症、肌张力障碍）、人格改变、逐渐丧失认知能力，并最终死亡。
For a long time, HD was thought to be a typical autosomal dominant condition with age-dependent penetrance.长期以来，HD被认为是一种典型的常染色体显性遗传病，具有年龄依赖性外显率。
The disease is transmitted from generation to generation with a 50% risk to each offspring.该病代代相传，每个后代有50%的发病风险。
Heterozygous and homozygous individuals carrying the abnormal allele have very similar phenotypes, although homozygotes may have a more rapid course of their disease.携带异常等位基因的杂合子和纯合子个体表型非常相似，尽管纯合子的病程可能更快。
There are, however, obvious peculiarities that cannot be explained by simple autosomal dominant inheritance.然而，存在一些明显的异常现象，无法用简单的常染色体显性遗传来解释。
First, the disease appears to develop at an earlier and earlier age in successive generations, a phenomenon referred to as anticipation.首先，该病在连续几代中发病年龄似乎越来越早，这种现象称为早现遗传。
Second, anticipation seems to occur only when the pathogenic allele is transmitted by an affected father and not by an affected mother, a situation known as parental transmission bias.其次，早现遗传似乎仅在致病等位基因由患病父亲传递时发生，而非由患病母亲传递，这种情况称为亲本传递偏倚。
The peculiarities of inheritance of HD are now readily explained by the discovery that the pathogenic allele is composed of an abnormally long CAG expansion in the coding region of the HTT gene.HD遗传的异常现象现在很容易通过以下发现来解释：致病等位基因由HTT基因编码区中异常长的CAG重复扩增组成。
Normal individuals carry alleles with between 9 and 35 CAG repeats in their HTT gene, with the average being 18 or 19.正常个体的HTT基因携带9至35个CAG重复的等位基因，平均为18或19个。
Individuals affected with HD, however, have 36 or more repeats, with the average being around 46.然而，HD患者具有36个或更多重复，平均约为46个。
Repeat numbers of 36 to 50 usually result in disease later in life, which explains the age-dependent penetrance that is a hallmark of this condition.重复数为36至50通常导致晚年发病，这解释了作为该病标志的年龄依赖性外显率。
A borderline repeat number of 36 to 39, although usually associated with HD, can be found in a few individuals who show no signs of the disease even at a fairly advanced age.临界重复数36至39虽然通常与HD相关，但在少数个体中发现，这些个体即使在相当高龄也未显示该病迹象。
The age of onset varies with how many CAG repeats are present . 20 40 60 80 Age at onset (years) Normal range ≤ 35 Reduced penetrance range 36–39 Fully penetrant range ≥ 40 20 30 40 50 60 70 80 90 100 110 120 Number of CAG repeats in HTT The solid line is the average age of onset, and the shaded area shows the range of age of onset for any given number of repeats.发病年龄随CAG重复数目而变化。20 40 60 80 发病年龄（年） 正常范围 ≤ 35 外显率降低范围 36-39 完全外显率范围 ≥ 40 20 30 40 50 60 70 80 90 100 110 120 HTT中CAG重复数目 实线表示平均发病年龄，阴影区域表示任意给定重复数目的发病年龄范围。
(Data courtesy Dr.（数据由Dr.
Macdonald, Massachusetts General Hospital, Boston.)Macdonald提供，马萨诸塞州总医院，波士顿。）
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How, then, does an individual come to have an expanded CAG repeat in his or her HTT gene?
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How, then, does an individual come to have an expanded CAG repeat in his or her HTT gene?那么，个体是如何在其HTT基因中获得扩增的CAG重复序列的呢？
First, the person may have inherited it from a parent who has an allele expanded beyond the normal range but has not yet developed the disease.首先，这个人可能从父母一方遗传了该重复序列，该亲本携带一个扩增超出正常范围但尚未发病的等位基因。
Second, the person may have inherited an expanded repeat from a parent with repeat length of 36 to 39 which may or may not cause disease in the parent’s lifetime but may have expanded on transmission, resulting in earlier-onset disease in later generations (i. e., anticipation).其次，这个人可能从父母一方遗传了一个扩增的重复序列，该亲本的重复长度为36至39，可能在其一生中致病也可能不致病，但在传递过程中可能进一步扩增，导致后代更早发病（即遗传早现）。
For example, in the pedigree shown in that can expand further during meiosis.例如，在所示的系谱中，减数分裂期间该重复序列可进一步扩增。
CAG repeat alleles at the upper limits of normal that do not cause disease but are capable of expanding into the disease-causing range are known as intermediate alleles (previously premutations).处于正常上限、不致病但能够扩增至致病范围的CAG重复等位基因称为中间等位基因（先前称为前突变）。
Expansion in HTT alleles shows a paternal transmission bias and occurs most frequently during male gametogenesis; thus, the severe early-onset juvenile form of the disease, seen with the largest expansions (70–121 repeats), is always paternally inherited.HTT等位基因的扩增表现出父系传递偏倚，且最常见于雄性配子生成过程中；因此，伴有最大扩增（70–121个重复）的严重早发型少年型疾病总是由父系遗传。
Fragile X Syndrome The fragile X syndrome (Case 17) is the most common heritable form of moderate intellectual disability.脆性X综合征 脆性X综合征（病例17）是最常见的遗传性中度智力残疾形式。
The name fragile X refers to a cytogenetic marker on the X chromosome at Xq 27. 3, a so-called fragile site induced in cultured cells in which the chromatin fails to condense properly during mitosis.名称“脆性X”指X染色体上Xq27.3处的一种细胞遗传学标记，即培养细胞中诱导的所谓脆性位点，此处染色质在有丝分裂过程中无法正常凝聚。
The syndrome is inherited as an X-linked disorder with penetrance in females in the 50 to 60% range.该综合征作为X连锁遗传病遗传，女性外显率在50%至60%范围内。
The fragile X syndrome has a frequency of 1 in 3000 to 4000 male births; it is so common that it requires consideration in the differential diagnosis of intellectual disability or autism in both males and females.脆性X综合征在男性新生儿中的发生率为1/3000至1/4000；因其常见，在男性和女性的智力残疾或自闭症的鉴别诊断中必须予以考虑。
Like HD, fragile X syndrome is caused by an unstable repeat expansion.与亨廷顿病类似，脆性X综合征由不稳定的重复序列扩增引起。
However, in this case, a massive expansion of a different triplet repeat, CGG, occurs in the 5′ untranslated region of a gene called FMR1.然而，在此情况下，另一种三核苷酸重复CGG的大量扩增发生在名为FMR1的基因的5′非翻译区。
The normal number of repeats is up to 55, whereas more than 200 (and even up to several thousand) repeats are found in individuals with the “full” fragile X syndrome allele.正常重复数为最多55个，而携带“完全”脆性X综合征等位基因的个体中发现超过200个（甚至多达数千个）重复。
The syndrome is due to a lack of expression of the FMR1 gene and failure to produce the encoded protein.该综合征是由于FMR1基因表达缺失及无法产生编码的蛋白质所致。
The expanded repeat leads to excessive methylation of cytosines in the promoter of FMR1.扩增的重复序列导致FMR1启动子中胞嘧啶过度甲基化。
As discussed in Chapter 3, DNA methylation at Cp G islands prevents normal promoter function and leads to gene silencing.如第3章所述，CpG岛上的DNA甲基化阻止正常启动子功能并导致基因沉默。
Triplet repeat numbers between 55 and 200 constitute an intermediate premutation stage of the fragile X syndrome.三核苷酸重复数在55至200之间构成脆性X综合征的中间前突变阶段。
Expansions in this range are unstable when they are transmitted from mother to child and have an increasing tendency to undergo full expansion to more than 200 copies of the repeat during gametogenesis in the female but almost never in the male.此范围内的扩增在从母亲向孩子传递时不稳定，且在女性配子生成过程中倾向于完全扩增至超过200个重复，但男性中几乎不发生。
The risk for expansion increases dramatically with increasing premutation size .扩增风险随着前突变大小的增加而急剧上升。
The overall premutation frequency in females in the population is estimated to be greater than 1 in 200. 100 80 60 40 20 Frequency of expansion to full mutation (%) Number of repeats in a premutation allele 60–69 80–89 >100 56–59 14% 20% 58% 72% 94% 100% 70–79 90–99 The risk for fragile X syndrome to her sons is approximately half this frequency because there is a 50% chance a son will inherit the expanded allele.人群中女性前突变的总体频率估计超过1/200。100 80 60 40 20 扩增至完全突变的频率(%) 前突变等位基因重复数 60–69 80–89 >100 56–59 14% 20% 58% 72% 94% 100% 70–79 90–99 其儿子患脆性X综合征的风险约为该频率的一半，因为儿子有50%的概率遗传扩增的等位基因。
The risk for fragile X syndrome to her daughters is approximately one-fourth this frequency because there is a 50% chance a daughter would inherit the full mutation, and penetrance of the full mutation in a female is ~50%.其女儿患脆性X综合征的风险约为该频率的四分之一，因为女儿有50%的概率遗传完全突变，且女性中完全突变的外显率约为50%。
(From Nolin SL: Familial transmission of the FMR1 CGG repeat, Am J Hum Genet 59:1252-1261, 1996.（来自Nolin SL：FMR1 CGG重复的家族性传递，Am J Hum Genet 59:1252-1261, 1996。）
The University of Chicago Press.) 25 2 1 1 2 3 4 5 37 42 70 55 103 I II Shown beneath the pedigree is a Southern blot analysis for CAG repeat expansions in the HTT gene.芝加哥大学出版社。）25 2 1 1 2 3 4 5 37 42 70 55 103 I II 系谱下方显示的是HTT基因中CAG重复扩增的Southern印迹分析。
In addition to a normal allele containing 25 CAG repeats, individual I-1 and his children, II-1, II-2, II-4, and II-5, are all heterozygous for expanded alleles, each containing a different number of CAG repeats.除了一个含有25个CAG重复的正常等位基因外，个体I-1及其子女II-1、II-2、II-4和II-5均为扩增等位基因的杂合子，每个等位基因含有不同数量的CAG重复。
The repeat number is indicated below each individual.每个个体下方标明了重复数。
II-2, II-4, and II-5 are all affected; individual II-1 is unaffected at the age of 50 years but will develop the disease later in life.II-2、II-4和II-5均受累；个体II-1在50岁时未发病，但将在以后的生活中发病。
(Data courtesy Dr.（数据由德克萨斯州休斯顿贝勒医学院Ben Roa博士提供。）
Ben Roa, Baylor College of Medicine, Houston, Texas.)[TL:missing]
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Patterns of Single-Gene Inheritance 129 Similarities and Differences in Huntington Disease and Fragile X Pedigrees A com…
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Patterns of Single-Gene Inheritance 129 Similarities and Differences in Huntington Disease and Fragile X Pedigrees A comparison of HD with the fragile X syndrome reveals some similarities but also many differences, illustrating many of the features of disorders due to dynamic mutations: Intermediate/Premutation expansions causing an increased risk for passing on full expansion alleles are the rule in both of these disorders.单基因遗传模式129：亨廷顿病与脆性X系谱的相似性与差异性 将HD与脆性X综合征进行比较，揭示了一些相似之处，但也存在许多差异，说明了动态突变所致疾病的许多特征：在这两种疾病中，中间/前突变扩增导致传递完全扩增等位基因的风险增加是普遍现象。
Anticipation is common in both.遗传早现在这两种疾病中均常见。
However, the number of repeats in intermediate alleles for HD is 29 to 35, far smaller than the 55 to 200 repeats in fragile X syndrome premutations.然而，HD中间等位基因中的重复次数为29至35，远小于脆性X综合征前突变中的55至200次重复。
Premutation carriers for fragile X syndrome are at risk for adult-onset ataxia (in males) and ovarian failure (in females).脆性X综合征的前突变携带者有发生成年起病的共济失调（男性）和卵巢早衰（女性）的风险。
Intermediate allele carriers in HD are, by definition, disease-free.根据定义，HD中间等位基因携带者是无疾病的。
The expansion of premutation alleles occurs primarily in the female germline in fragile X syndrome; in contrast, the largest expansions causing juvenileonset HD occur in the male germline.在脆性X综合征中，前突变等位基因的扩增主要发生在女性生殖系；相反，导致青少年起病HD的最大扩增发生在男性生殖系。
MATERNAL INHERITANCE OF DISORDERS CAUSED BY VARIANTS IN THE MITOCHONDRIAL GENOME All the patterns of inheritance described thus far are explained by variants in the nuclear genome, in either autosomal or X-linked genes.线粒体基因组变异所致疾病的母系遗传：迄今为止描述的所有遗传模式均由核基因组中的变异解释，无论是常染色体基因还是X连锁基因。
However, some inherited diseases that do not show patterns typical of mendelian inheritance are caused by pathogenic variants in the mitochondrial genome (mtDNA), which manifest strictly maternal inheritance.然而，一些不表现出典型孟德尔遗传模式的遗传性疾病是由线粒体基因组（mtDNA）中的致病变异引起的，这些疾病表现为严格的母系遗传。
Disorders caused by pathogenic variants in mtDNA have several unusual features that result from the unique characteristics of mitochondrial biology and function.由mtDNA致病变异引起的疾病具有若干不寻常的特征，这些特征源于线粒体生物学和功能的独特特性。
As introduced in Chapter 2, not all the RNA and protein synthesized in a cell are encoded in the DNA of the nucleus; a small but important fraction is encoded by genes in mtDNA.如第2章所述，细胞中合成的RNA和蛋白质并非全部由核DNA编码；一小部分但重要的部分是由mtDNA中的基因编码的。
The mitochondrial genome consists of 37 genes that encode 13 subunits of enzymes involved in oxidative phosphorylation, as well as ribosomal RNAs and transfer RNAs required for translating the transcripts of the mitochondria-encoded polypeptides.线粒体基因组由37个基因组成，这些基因编码参与氧化磷酸化的酶的13个亚基，以及翻译线粒体编码多肽转录本所需的核糖体RNA和转移RNA。
Because mitochondria are essential to the normal functioning of nearly all cells, disruption of energy production by pathogenic variants in mtDNA often results in severe disease, affecting many different tissues.由于线粒体对几乎所有细胞的正常功能至关重要，mtDNA致病变异破坏能量产生常常导致严重疾病，影响许多不同组织。
Thus, pleiotropy is the rule, not the exception, in mitochondrial disorders.因此，多效性在线粒体疾病中是普遍规律，而非例外。
More than 100 different pathogenic variants have been identified in mtDNA that can cause a range of human diseases—often involving the central nervous and musculoskeletal systems, such as myoclonic epilepsy with ragged-red fibers (Case 33).已在mtDNA中鉴定出超过100种不同的致病变异，可导致一系列人类疾病——通常涉及中枢神经系统和肌肉骨骼系统，例如伴有破碎红纤维的肌阵挛性癫痫（病例33）。
In this section we will focus on the distinctive pattern of inheritance related to three unusual features of mtDNA: maternal inheritance, replicative segregation, and homoplasmy and heteroplasmy.在本节中，我们将重点关注与mtDNA三个不寻常特征相关的独特遗传模式：母系遗传、复制分离以及同质性和异质性。
The underlying mechanisms of mitochondrial disorders are discussed in more detail in Chapter 13.线粒体疾病的潜在机制在第13章中有更详细的讨论。
Maternal Inheritance of mtDNA The first defining characteristic of the genetics of mtDNA is its maternal inheritance.mtDNA的母系遗传 mtDNA遗传学的第一个定义性特征是其母系遗传。
Sperm mitochondria are generally not present in the zygote so that only the maternal mtDNA is transmitted to the next generation.精子线粒体通常不存在于受精卵中，因此只有母系mtDNA被传递到下一代。
Thus, the children of a female who has an mtDNA variant may inherit it, whereas none of the offspring of a male carrying the same variant will.因此，携带mtDNA变异的女性其子女可能遗传该变异，而携带相同变异的男性其后代则不会遗传。
Pedigrees of such disorders are quite distinctive, as shown by the strictly maternal inheritance of an mtDNA variant causing Leber hereditary optic neuropathy .此类疾病的系谱相当独特，如导致Leber遗传性视神经病变的mtDNA变异的严格母系遗传所示。
Although maternal inheritance is the general expectation, at least one instance of paternal inheritance of mtDNA has occurred in a patient with a mitochondrial myopathy.尽管母系遗传是普遍预期，但至少有一例mtDNA父系遗传发生在一位线粒体肌病患者身上。
Consequently, in individuals with apparently sporadic mtDNA mutations, the rare occurrence of paternal mtDNA inheritance must be considered (4).因此，在表现为散发性mtDNA突变的个体中，必须考虑罕见的父系mtDNA遗传（4）。
Replicative Segregation A second feature of the mitochondrial genome is the stochastic nature of segregation during mitosis and meiosis.复制分离：线粒体基因组的第二个特征是在有丝分裂和减数分裂过程中分离的随机性。
The number of mtDNA copies per cell is not fixed and is substantially higher than the number of nuclear DNA copies, with cells having as many as hundreds of thousands of mtDNA copies.每个细胞中mtDNA拷贝数不是固定的，且远高于核DNA拷贝数，细胞可拥有多达数十万个mtDNA拷贝。
In addition there is no fixed phase of the cell cycle for the replication of mtDNA.此外，mtDNA的复制没有固定的细胞周期时相。
At cell division, the copies of mtDNA in each of the I II III Inheritance is only through the maternal lineage, in agreement with the known maternal inheritance of mitochondrial DNA.在细胞分裂时，每个I II III中的mtDNA拷贝的遗传仅通过母系进行，这与已知的线粒体DNA母系遗传一致。
Note that no affected male transmits the disease.注意，没有受影响的男性传递该疾病。
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mitochondria in each cell sort randomly to the daughter cells, in stark contrast to the highly predictable and programme…
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mitochondria in each cell sort randomly to the daughter cells, in stark contrast to the highly predictable and programmed segregation of the 46 nuclear chromosomes.每个细胞中的线粒体随机分配到子细胞中，这与46条核染色体的高度可预测和程序性分离形成鲜明对比。
This process is known as replicative segregation and can result in significant variability in manifestations of mitochondrial disorders among different tissues and/or individuals.这一过程被称为复制分离，可导致线粒体疾病在不同组织和/或个体中的表现出现显著变异。
Homoplasmy and Heteroplasmy The presence of a high copy number creates an additional distinctive feature in the genetics of mtDNA.同质性与异质性 高拷贝数的存在为mtDNA遗传学创造了另一个独特特征。
The terms heterozygous and homozygous, used to describe the presence of one or two allelic variants of a nuclear gene, are inexact for mtDNA.用于描述核基因一个或两个等位变异存在的术语杂合和纯合，对于mtDNA而言并不精确。
Instead, the term for the uniform presence of an identical mitochondrial sequence is homoplasmic.相反，描述同一线粒体序列均一存在的术语是同质性（homoplasmic）。
When a variant sequence of mtDNA is also present, within a cell, tissue, or organism, the term used to describe this is heteroplasmic.当mtDNA的变异序列也存在于细胞、组织或生物体内时，用于描述这一情况的术语是异质性（heteroplasmic）。
When a sequence variant first occurs in the mtDNA, it is present in only one of the mtDNA molecules in a mitochondrion.当序列变异首次出现在mtDNA中时，它仅存在于一个线粒体内的一个mtDNA分子中。
As mtDNA replicates, the mitochondria undergo fission and fusion, and the variant and wild-type DNA are distributed randomly into daughter organelles, which – simply by chance – may contain different proportions of the two allelic variants.随着mtDNA复制，线粒体经历分裂和融合，变异型和野生型DNA被随机分配到子代细胞器中——这些子代细胞器可能纯属偶然地含有不同比例的两个等位变异。
The cell, which now contains mitochondria containing different mixtures of mtDNAs, in turn distributes those mitochondria randomly to its daughter cells.此时含有不同mtDNA混合物的线粒体的细胞，进而将这些线粒体随机分配给其子细胞。
Daughter cells may thus have different levels of heteroplasmy .因此子细胞可能具有不同程度的异质性。
A key feature of the heteroplasmic state is that the ratio of the two allelic variants is not fixed over time and may change with further replication and cell division.异质性状态的一个关键特征是：两种等位变异的比例并非随时间固定不变，且可能随着进一步的复制和细胞分裂而改变。
Because the phenotypic expression of a pathogenic variant in mtDNA depends on a quantitative value—the relative proportions of normal- and pathogenic-allele- bearing mtDNA in the cells making up different tissues—reduced penetrance and variable expression are typical features of mitochondrial disorders (Case 33).由于mtDNA中致病性变异的表型表达取决于一个定量值——即构成不同组织的细胞中携带正常等位基因和致病等位基因的mtDNA的相对比例——因此降低的外显率和可变表达是线粒体疾病的典型特征（病例33）。
Most pathogenic variants in mtDNA are only present and transmitted in a state of heteroplasmy, since they would reduce reproductive fitness to 0 if they were homoplasmic.mtDNA中的大多数致病性变异仅以异质性状态存在和传递，因为如果它们是同质性的，将会将生殖适合度降至0。
The exceptions (including Leber hereditary optic neuropathy as described earlier) cause disorders that are either incompletely penetrant or are not reproductively lethal.例外情况（包括如前所述的Leber遗传性视神经病变）所引起的疾病要么是不完全外显的，要么在生殖上非致命。
Maternal inheritance in the presence of heteroplasmy in the mother is associated with additional features of mtDNA genetics that are of medical significance.母亲存在异质性时的母系遗传与mtDNA遗传学的其他具有医学意义的特征相关。
First, the number of mtDNA molecules within developing oocytes is reduced before being subsequently amplified to the massive number (up to 106 copies) seen in mature oocytes.首先，发育中的卵母细胞内mtDNA分子数量减少，随后被扩增至成熟卵母细胞中可见的巨大数量（高达10^6拷贝）。
This restriction and subsequent amplification of mtDNA during oogenesis is termed the mitochondrial genetic bottleneck.卵子发生过程中mtDNA的这种限制及其后的扩增被称为线粒体遗传瓶颈。
Consequently, variability in the proportion of variant mtDNA molecules seen in the offspring of a mother with heteroplasmy arises, at least in part, from the sampling of a reduced subset of the mtDNAs after the mitochondrial bottleneck that occurs in oogenesis.因此，在具有异质性的母亲的子代中观察到的变异mtDNA分子比例变异，至少部分源于卵子发生过程中线粒体瓶颈之后对减少的mtDNA亚群进行的抽样。
The heteroplasmy of the resulting oocytes is a distribution of values based on the heteroplasmy of the mother herself.由此产生的卵母细胞的异质性是基于母亲自身异质性的一组值的分布。
As might be expected, mothers with a high heteroplasmy for a pathogenic variant are more likely to have clinically affected offspring than are mothers with a lower proportion.正如所料，对于致病性变异具有高异质性的母亲比具有较低比例的母亲更可能有临床受累的子代。
Mothers may also have offspring who, by chance, are homoplasmic for the absence of a pathogenic variant.母亲也可能有子代偶然因缺乏致病性变异而呈同质性。
Mutant mitochondria Normal mitochondria Clonal mtDNA proliferation Random Segregation N Disease phenotype Normal phenotype Threshold for phenotypic expression N N N N N Random partitioning of variant and wild-type mtDNA through multiple rounds of mitosis produces a collection of daughter cells with wide variation in heteroplasmy.突变型线粒体 正常型线粒体 克隆性mtDNA增殖 随机分离 N 疾病表型 正常表型 表型表达阈值 N N N N N 通过多轮有丝分裂，变异型和野生型mtDNA的随机分配产生了一组异质性广泛变化的子细胞。
Cell and tissue dysfunction results when the fraction of mitochondria that are carrying a variant exceeds a threshold level.当携带变异的线粒体比例超过阈值水平时，会导致细胞和组织功能障碍。
N, Nucleus.N，细胞核。
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Patterns of Single-Gene Inheritance 131 CORRELATING GENOTYPE AND PHENOTYPE An important component of medical genetics is…
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Patterns of Single-Gene Inheritance 131 CORRELATING GENOTYPE AND PHENOTYPE An important component of medical genetics is identifying and characterizing the genotypes responsible for particular disease phenotypes.单基因遗传模式 131 基因型与表型的关联 医学遗传学的一个重要组成部分是识别和表征导致特定疾病表型的基因型。
In doing so, it is important not to adhere to an overly simplistic view that each disease phenotype is caused uniquely by one particular variant in a specific gene or that pathogenic variants in a particular gene always cause the same phenotype.在此过程中，重要的是不要坚持一种过于简化的观点，即每种疾病表型都由特定基因中的一种特定变异唯一引起，或者特定基因中的致病性变异总是导致相同的表型。
In fact, there is often substantial heterogeneity in the complex relationship(s) among disease phenotypes, the genes that are altered in those diseases, and the nature of the variants found in those genes.事实上，疾病表型、这些疾病中发生改变的基因以及这些基因中发现的变异性质之间的复杂关系常常存在显著的异质性。
Three main types of heterogeneity are distinguished, as will be illustrated in detail in Chapters 12 and 13.主要区分出三种类型的异质性，正如将在第12章和第13章中详细说明的那样。
Here, we introduce them and outline their distinguishing features.在此，我们介绍它们并概述其区分特征。
Allelic heterogeneity, in which different variants in a gene may produce the same phenotype Locus heterogeneity, in which variants in different genes may cause the same phenotype Clinical or phenotypic heterogeneity, also referred to as a phenotypic diversity at a locus, in which different variants in a gene may result in different phenotypes Allelic Heterogeneity There may be more than one pathogenic variant at a locus.等位基因异质性，即同一基因中的不同变异可能产生相同的表型；位点异质性，即不同基因中的变异可能引起相同的表型；临床或表型异质性，也称为位点处的表型多样性，即同一基因中的不同变异可能导致不同的表型。等位基因异质性：一个位点上可能存在不止一种致病性变异。
Allelic heterogeneity may be responsible for differences in the severity or degree of pleiotropy demonstrated for a particular condition.等位基因异质性可能解释特定疾病所表现出的严重程度或多效性程度的差异。
As one example, more than 2000 different variants have been found worldwide in the cystic fibrosis transmembrane conductance regulator gene (CFTR) among patients with CF (Case 12).例如，在世界范围内的囊性纤维化患者中，已在囊性纤维化跨膜传导调节因子基因（CFTR）中发现了超过2000种不同的变异（病例12）。
Sometimes these different variants result in clinically indistinguishable disorders.有时这些不同的变异导致临床上无法区分的疾病。
In other cases, different variants at the same locus produce a similar phenotype but along a continuum of severity.在其他情况下，同一基因座上的不同变异产生相似的表型，但严重程度呈连续变化。
In autosomal recessive disorders, in particular, the fact that many individuals are compound heterozygotes for two different alleles further adds to phenotypic variability of a disorder.特别是在常染色体隐性遗传病中，许多个体是两个不同等位基因的复合杂合子，这一事实进一步增加了疾病的表型变异性。
For example, homozygotes or compound heterozygotes for many CFTR variants have classic CF with pancreatic insufficiency, severe progressive lung disease, and congenital absence of the vas deferens in males, whereas others with combinations of other variants may have lung disease but normal pancreatic function; still others will have only the abnormality of the male reproductive tract.例如，许多CFTR变异纯合子或复合杂合子患者表现为典型的囊性纤维化，伴有胰腺功能不全、严重进展性肺疾病和男性先天性输精管缺如；而其他携带不同变异组合的患者可能仅有肺疾病但胰腺功能正常；还有部分患者仅表现为男性生殖道异常。
Allelic heterogeneity may also manifest in the pattern of inheritance demonstrated for a particular condition.等位基因异质性也可能表现为特定疾病所显示的遗传模式。
For example, in retinitis pigmentosa, a common cause of hereditary visual impairment due to photoreceptor degeneration, some variants in the ORP1 gene, encoding an oxygen-regulated photoreceptor protein, cause an autosomal recessive form of the disease, whereas others in the same gene result in an autosomal dominant form.例如，在视网膜色素变性（一种由感光细胞变性引起的遗传性视力损害的常见原因）中，编码氧调控感光细胞蛋白的ORP1基因的某些变异导致常染色体隐性遗传形式的疾病，而同一基因中的其他变异则导致常染色体显性遗传形式。
Locus Heterogeneity Locus heterogeneity describes the situation in which clinically similar and even indistinguishable disorders may arise from variants in different loci in different individuals.位点异质性 位点异质性描述的是不同个体中不同位点的变异可能导致临床上相似甚至无法区分的疾病的情况。
For some phenotypes, pedigree analysis alone has been sufficient to demonstrate locus heterogeneity.对于某些表型，仅凭系谱分析就足以证明位点异质性。
Taking retinitis pigmentosa again as an example, it was recognized many years ago that the disease occurs in both autosomal and X-linked forms.再次以视网膜色素变性为例，多年前就已认识到该疾病有常染色体遗传和X连锁遗传两种形式。
Now, pedigree analysis combined with gene mapping has demonstrated that this single clinical entity can be caused by variants in at least 96 different genes, of which 89 are autosomal, 6 are X linked, and one is Y linked!如今，系谱分析结合基因定位已证明这一单一临床实体可由至少96个不同基因的变异引起，其中89个为常染色体基因，6个为X连锁基因，1个为Y连锁基因！
Clinical Heterogeneity Different variants in the same gene may produce very dissimilar phenotypes in different families: a phenomenon known as clinical or phenotypic heterogeneity.临床异质性 同一基因中的不同变异可能在不同家系中产生非常不相似的表型：这种现象称为临床或表型异质性。
This situation occurs with variants in the LMNA gene, which encodes a nuclear membrane protein.这种情况发生在编码核膜蛋白的LMNA基因的变异中。
Different LMNA variants have been associated with at least a half dozen phenotypically distinct disorders, including a form of muscular dystrophy, one form of hereditary dilated cardiomyopathy, one form of the Charcot-Marie-Tooth peripheral neuropathy, a disorder of adipose tissue called lipodystrophy, and the premature aging syndrome known as Hutchinson-Gilford progeria.不同的LMNA变异已与至少六种表型不同的疾病相关，包括一种肌营养不良症、一种遗传性扩张型心肌病、一种夏科-马里-图斯周围神经病变、一种称为脂肪营养不良的脂肪组织疾病，以及一种称为哈钦森-吉尔福德早衰症的早衰综合征。
IMPORTANCE OF THE FAMILY HISTORY IN MEDICAL PRACTICE Among medical specialties, medical genetics is distinctive in that it focuses not only on the patient but on the entire family.家族史在临床实践中的重要性 在医学专科中，医学遗传学的独特之处在于它不仅关注患者，还关注整个家庭。
A comprehensive family history is an important first step in the analysis of any disorder, regardless of whether the disorder is known to be genetic.全面的家族史是分析任何疾病的重要第一步，无论该疾病是否已知为遗传性。
As the late Barton Childs stated succinctly: “to fail to 4 CHARACTERISTICS OF MITOCHONDRIAL INHERITANCE All children of a female homoplasmic for a pathogenic variant will inherit the variant; the children of a male carrying a similar variant will not.正如已故的Barton Childs简洁地指出的那样：“如果未能……线粒体遗传的特征 女性纯质体携带致病性变异的所有子女都将遗传该变异；男性携带类似变异的子女则不会。
Females heteroplasmic for a pathogenic variant will pass the variant on to many of their children.异质体携带致病性变异的女性会将该变异传递给她的许多子女。
The heteroplasmy in her offspring is based on a distribution and cannot be easily predicted in advance.其后代中的异质性基于分布情况，难以提前预测。
The fraction of pathogenic variant, and therefore the risk and severity of disease, can vary considerably depending on the quantitative level of maternal heteroplasmy, as well as on random chance due to the oocyte bottleneck.致病性变异的比例，以及因此的疾病风险和严重程度，可因母体异质性水平以及卵母细胞瓶颈随机因素而有显著差异。
The heteroplasmy in different tissues of an individual can vary tremendously, thereby causing a spectrum of disease among the members of a family.个体不同组织中的异质性可能有巨大差异，从而导致家族成员中出现疾病谱。
Pleiotropy and variable expressivity in different affected family members are also frequent.受影响家族成员中的多效性和可变表达性也常见。
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take a good family history is bad medicine.” Despite the sophisticated cytogenetic, molecular, and genome testing now av…
Ch7 — Segment 24
take a good family history is bad medicine.” Despite the sophisticated cytogenetic, molecular, and genome testing now available to geneticists, an accurate family history (including the family pedigree) still remains a fundamental tool for all physicians and genetic counselors.[TL:failed]
They use it for determining the pattern of inheritance of a disorder in the family, forming a differential diagnosis, determining what genetic testing might be needed, and designing an individualized management and treatment plan for their patients.[TL:failed]
Furthermore, recognizing a familial component to a medical disorder allows the risk in other family members to be estimated so that proper management, prevention, and counseling can be offered to the patient and the family, as we will discuss in many of the chapters to follow.[TL:failed]
ACKNOWLEDGMENT We thank Carolyn Applegate, Jodie Vento and Cheryl Shuman for contributing to this chapter.[TL:failed]
GENERAL REFERENCES Bennett RL, French KS, Resta RG, et al: Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors, J Genet Counsel 17:424–433, 2008.[TL:failed]
Online Mendelian Inheritance in Man (OMIM), Baltimore, 2022, Johns Hopkins University, Rimoin DL, Pyeritz RE, Korf BR, editors: Emery and Rimoin’s essential medical genetics, Oxford, 2013, Academic Press.[TL:failed]
Scriver CR, Beaudet AL, Sly WS, et al: The metabolic and molecular bases of inherited disease, ed 8, New York, 2000, Mc Graw Hill.[TL:failed]
Updated online version available at PROBLEMS 1.[TL:failed]
Cathy and Calvin are pregnant for the second time.[TL:failed]
Their first child, Donald, has cystic fibrosis (CF).[TL:failed]
Cathy has two brothers, Charles and Colin, and a sister, Cindy.[TL:failed]
Colin and Cindy are unmarried.[TL:failed]
Charles is married to an unrelated woman, Carolyn, and has a 2-year-old daughter, Debbie.[TL:failed]
Cathy’s parents are Bob and Betty.[TL:failed]
Betty’s sister Barbara is the mother of Cathy’s husband, Calvin.[TL:failed]
There is no family history of CF except for Donald. a.[TL:failed]
Sketch the pedigree, using standard symbols. b.[TL:failed]
Which people in this pedigree are obligate heterozygotes?[TL:failed]
Which are likely heterozygotes?[TL:failed]
George and Grace, who have normal hearing, have eight children; two of their five daughters and two of their three sons have congenital hearing loss.[TL:failed]
Another couple, Harry and Helen, both with normal hearing, also have eight children; two of their six daughters and one of their two sons are hearing impaired.[TL:failed]
A third couple, Gilbert and Gisele, each with congenital hearing loss, have four children, who are all affected by hearing loss.[TL:failed]
Gilbert and Gisele’s daughter Hedy marries Horace, a hearing impaired son of George and Grace, and Hedy and Horace in turn have four hearing impaired children.[TL:failed]
Hedy and Horace’s eldest son Isaac marries Ingrid, a daughter of Harry and Helen; although both Isaac and Ingrid are hearing impaired, their six sons all have normal hearing.[TL:failed]
Sketch the pedigree and answer the following questions.[TL:failed]
(Hint: How many different types of congenital hearing loss are segregating in this pedigree?) a.[TL:failed]
State the probable genotypes of Isaac and Ingrid’s children. b.[TL:failed]
Why are all the children of Gilbert and Gisele and of Hedy and Horace hearing impaired?[TL:failed]
Consider the following situations: a.[TL:failed]
Retinitis pigmentosa occurs in X-linked and autosomal forms. b.[TL:failed]
Two parents each have a typical case of familial hypercholesterolemia: hypercholesterolemia, arcus corneae, tendinous xanthomas, and deficiency of low- density lipoprotein (LDL) receptors, and family history of the disorder.[TL:failed]
Their child has very high plasma cholesterol level at birth and within a few years develops xanthomas and generalized atherosclerosis. c.[TL:failed]
A couple with normal vision, from an isolated community, have a child with autosomal recessive gyrate atrophy of the retina.[TL:failed]
The child grows up, marries another member (with normal vision) of the same community, and has a child with the same eye disorder. d.[TL:failed]
A child has severe neurofibromatosis 1 (NF1).[TL:failed]
Her father is phenotypically normal; her mother seems clinically normal but has several large café au lait spots and areas of hypopigmentation; slit-lamp examination shows a few Lisch nodules (hamartomatous growths on the iris). e.[TL:failed]
Parents of normal stature have a child with achondroplasia. f.[TL:failed]
An adult male with myotonic dystrophy has cataracts, frontal balding, and hypogonadism, in addition to myotonia. g.[TL:failed]
A man with vitamin D -resistant rickets transmits the condition to all his daughters, who have a milder form of the disease than their father; none of his sons is affected.[TL:failed]
The daughters have approximately equal numbers of unaffected sons, affected sons, unaffected daughters, and affected daughters, the affected sons being more severely affected than their affected sisters. h.[TL:failed]
A boy has progressive muscular dystrophy with onset in early childhood and is wheelchair-bound by age 12 years.[TL:failed]
An unrelated man also has progressive muscular dystrophy but is still ambulant at the age of 30 years.[TL:failed]
Molecular analysis shows that the individuals have a large but different deletion in the dystrophin gene.[TL:failed]
Which of the concepts listed here are illustrated by situations a. to h.?[TL:failed]
Variable expressivity Consanguinity X-linked dominant inheritance New mutation Allelic heterogeneity Locus heterogeneity Homozygosity for an autosomal dominant trait Pleiotropy 4.[TL:failed]
Don and his maternal grandfather Barry both have hemophilia A.[TL:failed]
Don’s partner Diane is his maternal first cousin.[TL:failed]
Don and Diane have one son, Edward, and two daughters, continued[TL:failed]
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Patterns of Single-Gene Inheritance 133 Elise and Emily, all of whom have hemophilia A.
Ch7 — Segment 25
Patterns of Single-Gene Inheritance 133 Elise and Emily, all of whom have hemophilia A.单基因遗传模式133 伊莉斯和艾米丽，她们均患有血友病A。
They also have an unaffected daughter, Enid. a.他们还有一个未受影响的女儿，伊妮德。a.
Draw the pedigree. b.绘制系谱图。b.
Why are Elise and Emily affected? c.为什么伊莉斯和艾米丽会患病？c.
What is the probability that a son of Elise would have hemophilia?伊莉斯的儿子患血友病的概率是多少？
What is the probability that her daughter would have hemophilia? d.她的女儿患血友病的概率是多少？d.
What is the probability that a son of Enid would have hemophilia?伊妮德的儿子患血友病的概率是多少？
A daughter?一个女儿？
A couple has a child with NF1.一对夫妇生了一个患有NF1的孩子。
Both parents are clinically normal, and neither of their families shows a positive family history. a.父母双方均临床正常，且双方家族均无阳性家族史。a.
What is the probable explanation for NF1 in their child? b.他们的孩子患NF1的可能解释是什么？b.
What is the risk for recurrence in other children of this couple? c.这对夫妇的其他孩子再发的风险是多少？c.
If the husband has another child by a different mother, what would the risk for NF1 be? d.如果丈夫与另一位母亲再生育一个孩子，患NF1的风险是多少？d.
What is the risk that any offspring of the affected child will also have NF1?患病孩子的任何后代患NF1的风险是多少？
Before starting her family, the consultand (arrow) wants to know the risk that a child of hers and her husband’s would have a birth defect because they are related (see pedigree).在组建家庭前，咨询者（箭头所指）想知道她和丈夫的孩子因近亲关系而出现出生缺陷的风险（参见系谱图）。
The family history reveals no known recessive disease.家族史未发现已知的隐性遗传病。
What is the chance that such a child could be homozygous for a variant for a recessive disorder carried by the woman who is her great-grandmother and her partner’s grandmother?这样的孩子有可能成为由她的曾祖母和伴侣的祖母携带的隐性遗传病变异的纯合子的几率是多少？
I II III IV V 7.I II III IV V 7.
Given the following pedigree, what is/are the most likely inheritance pattern(s); possible but less likely inheritance pattern(s); incompatible inheritance pattern(s)?给定以下系谱图，最可能的遗传模式是什么；可能但可能性较小的遗传模式；不可能的遗传模式？
Patterns are autosomal recessive, autosomal dominant, X-linked recessive, X-linked dominant, and mitochondrial.模式包括常染色体隐性遗传、常染色体显性遗传、X连锁隐性遗传、X连锁显性遗传和线粒体遗传。
Justify your choices.证明你的选择。
I II III PROBLEMS—CONT’D .I II III 问题——续。

Principles of Clinical Epigenetics

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Principles of Clinical Epigenetics Sarah Goodman Cheryl Cytrynbaum Rosanna Weksberg INTRODUCTION Epigenetics is a nascen…
Ch8 — Segment 26
Principles of Clinical Epigenetics Sarah Goodman Cheryl Cytrynbaum Rosanna Weksberg INTRODUCTION Epigenetics is a nascent and quickly evolving field.临床表观遗传学原理 莎拉·古德曼 谢丽尔·西特林鲍姆 罗斯安娜·韦克斯伯格 引言 表观遗传学是一个新兴且快速发展的领域。
As defined in Chapter 3, epigenetics refers to the study of modifications to DNA or DNA packaging that are transmissible to daughter cells and that do not involve changes to the DNA sequence.如第三章所定义，表观遗传学是指研究可传递给子细胞且不涉及DNA序列改变的DNA或其包装修饰的学科。
A variety of epigenetic marks and phenomena were described earlier, including (1) post-translational modifications of histone proteins, including acetylation, phosphorylation, and methylation; (2) modifications to DNA, such as DNA methylation (also referred to as 5-­methylcytosine [5m C]); (3) noncanonical histone variants; (4) noncoding RNAs (e. g., long noncoding RNAs and micro RNAs); and (5) X chromosome inactivation.前文描述了多种表观遗传标记和现象，包括：(1)组蛋白的翻译后修饰，如乙酰化、磷酸化和甲基化；(2)DNA修饰，如DNA甲基化（也称5-甲基胞嘧啶[5mC]）；(3)非典型组蛋白变体；(4)非编码RNA（例如长链非编码RNA和微小RNA）；以及(5)X染色体失活。
Together, the DNA and histone modifications, as well as molecules that support three-­dimensional (3D) DNA structure, constitute the epigenome.DNA与组蛋白修饰以及支持三维DNA结构的分子共同构成了表观基因组。
To that end, many of these epigenetic marks function in gene regulation by altering the structure of DNA and establishing heterochromatin vs. euchromatin.为此，许多此类表观遗传标记通过改变DNA结构并建立异染色质与常染色质，在基因调控中发挥作用。
This modulation of the structural organization of DNA, affecting DNA accessibility and gene expression, orchestrates the cellular and temporal processes that drive normal development, including cell differentiation and steady-­state variation in differentiated cells.这种对DNA结构组织的调控影响DNA的可及性和基因表达，从而协调驱动正常发育的细胞和时间过程，包括细胞分化及分化细胞中的稳态变异。
In this chapter we describe specific topics in the emerging field of clinical epigenetics—­that is, the role of epigenetics specifically as it relates to the mechanistic underpinnings of human health and disease.本章我们将阐述临床表观遗传学这一新兴领域中的特定主题——即表观遗传学在人类健康与疾病机制基础中的具体作用。
Our current use of the term epigenetics is quite similar to the original definition described by Conrad Waddington in the 1940s; epigenetics is “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being.” Today, the term also encompasses the idea of cellular memory (i. e., molecular changes that are stable and persist long after the original exposure is no longer present), which is especially pertinent to understanding the mechanistic link between environmental exposures, altered gene regulation, and phenotypic outcomes such as increased morbidity and mortality.我们目前对“表观遗传学”一词的使用与康拉德·沃丁顿在20世纪40年代提出的原始定义相当接近：表观遗传学是“研究基因及其产物之间因果相互作用，从而产生表型的生物学分支”。如今，该术语还包含细胞记忆的概念（即分子变化稳定存在，并在初始暴露消失后长期持续），这对于理解环境暴露、基因调控改变与表型结果（如发病率和死亡率升高）之间的机制联系尤为重要。
It is now recognized that there are established pairwise associations between phenotype, genetic variation, epigenetic patterns, and environmental influence that lead us to the central dogma of epigenetics: Epigenetic patterning reflects the relationship between genetic variation and the environment and therefore represents a regulatory stratum above the genome responsible for many types of phenotypic variability.现已认识到，表型、遗传变异、表观遗传模式与环境影响之间存在确定的成对关联，这引出了表观遗传学的中心法则：表观遗传模式反映了遗传变异与环境之间的关系，因此代表基因组之上负责多种表型变异的调控层次。
The field has also generated a new vocabulary, often modifying words from the field of genetics, to codify these newly described phenomena (see 1 for definitions of common epigenetic terms used in this chapter)..该领域还产生了新词汇，常通过修改遗传学领域的词汇来编码这些新描述的现象（参见表1了解本章所用常见表观遗传学术语的定义）。
LIST OF COMMON EPIGENETICS TERMS WITH DEFINITIONS Cp G or Cp G site: a cytosine guanine dinucleotide (i. e., a C nucleotide followed by a G nucleotide in the DNA sequence oriented 5′ to 3′).常见表观遗传学术语及定义列表 CpG或CpG位点：一个胞嘧啶-鸟嘌呤二核苷酸（即DNA序列中5'→3'方向上一个C核苷酸后跟一个G核苷酸）。
Cytosines in Cp G dinucleotides can be methylated, making 5-­methylcytosines.CpG二核苷酸中的胞嘧啶可被甲基化，形成5-甲基胞嘧啶。
Cp G methylation is the most abundant form of DNA methylation, although there is non-­Cp G methylation.CpG甲基化是最丰富的DNA甲基化形式，尽管也存在非CpG甲基化。
DMR (differentially methylated region): a set of Cp Gs within a defined locus, which differs between samples; samples used to identify DMRs may differ by tissue type, phenotype, exposure, etc.DMR（差异甲基化区域）：指特定基因座内的一组CpG位点，在不同样本间存在差异；用于鉴定DMR的样本可因组织类型、表型、暴露等因素而异。
DMRs are regarded as possible functional regions involved in gene transcriptional regulation, especially when they overlap gene regulatory regions, such as promoters or enhancers.DMR被认为是参与基因转录调控的可能功能区域，尤其是当它们与基因调控区域（如启动子或增强子）重叠时。
DNA methylation: the addition of a methyl group, typically to the cytosine in a Cp G at position C5, creating 5-­methylcytosines.DNA甲基化：甲基基团的添加，通常加至CpG中胞嘧啶的C5位，生成5-甲基胞嘧啶。
Addition of methyl groups to DNA is carried out by DNA methyltransferases.向DNA添加甲基基团由DNA甲基转移酶催化完成。
Epigenome: the complete set of (described and undescribed) epigenetic marks.表观基因组：全部（已描述和未描述的）表观遗传标记的集合。
Each cell type carries a unique epigenome, which contributes to cellular identity.每种细胞类型携带独特的表观基因组，这决定了细胞的特性。
Epimutation: a disease-­related change in DNA methylation, often occurring at an imprinted locus.表观突变：与疾病相关的DNA甲基化改变，常发生在印记基因座。
EWAS (epigenome-­wide association analysis): a research methodology that takes its name from genome-­wide association analysis, in which variation in an epigenetic mark is assessed against a phenotype of interest.EWAS（表观基因组关联分析）：一种研究方法，其命名源于全基因组关联分析，通过评估表观遗传标记的变异与目标表型之间的关联。
Imprinted domain: a cluster of imprinted genes and associated regulatory elements, including an imprinting center.印记结构域：一组印记基因及相关的调控元件（包括印记中心）的簇集。
Imprinting center: regulatory regions of varying DNA methylation levels established in the germline that act as master cis-­regulatory elements to local regions of imprinted genes.印记中心：在生殖系中建立的不同DNA甲基化水平的调控区域，作为局部印记基因区域的顺式主调控元件。
Also called imprinting control region.也称为印记控制区。
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Recent work in epigenetics has highlighted the role of epigenetics in human health outcomes, specifically the relationsh…
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Recent work in epigenetics has highlighted the role of epigenetics in human health outcomes, specifically the relationship between DNA methylation and genetic variation, including genetic background or population-­ level variation, polygenic risk scores, and single deleterious gene variants.表观遗传学近期的研究强调了表观遗传学在人类健康结局中的作用，特别是DNA甲基化与遗传变异之间的关系，包括遗传背景或群体水平变异、多基因风险评分以及单个有害基因变异。
In this context, a risk allele can predispose individuals to a certain outcome or phenotype following an exposure, such as an adverse reaction to a medication; the underlying mechanism that drives this reaction may be epigenetic in nature and function via DNA methylation and histone modification changes.在此背景下，风险等位基因可使个体在暴露后易患某种结局或表型，例如对药物的不良反应；驱动这种反应的潜在机制可能在本质上具有表观遗传性，并通过DNA甲基化和组蛋白修饰变化起作用。
As such, if we were to measure DNA methylation in a group of individuals with and without the risk allele, with and without exposure to the medication, the methylation patterns would reflect not just the allele or the exposure, but both.因此，如果我们测量一组携带和不携带风险等位基因、暴露和未暴露于药物的个体的DNA甲基化，甲基化模式不仅反映等位基因或暴露，而是反映两者。
These so-­called epialleles represent important biomarkers of the past exposure and may be valuable in a clinical setting.这些所谓的表观等位基因代表了过去暴露的重要生物标志物，在临床环境中可能具有价值。
For example, epialleles could provide biologic validation of an exposure to a specific toxin, such as a past exposure to secondhand cigarette smoke in an individual with a respiratory disease and a negative smoking history.例如，表观等位基因可提供对特定毒素暴露的生物学验证，例如患有呼吸系统疾病且无吸烟史的个体过去暴露于二手烟的情况。
EPIGENETIC MACHINERY The epigenetic machinery within cells consists of a set of enzymes with specific functions that maintain transcriptional programs and 3D DNA structure, collectively known as epigenetic regulators.表观遗传机制 细胞内的表观遗传机制由一组具有特定功能的酶组成，这些酶维持转录程序和三维DNA结构，统称为表观遗传调控因子。
Later in the chapter we focus on the epigenetics regulators involved in histone post-translational modifications and DNA methylation.本章稍后将重点讨论参与组蛋白翻译后修饰和DNA甲基化的表观遗传调控因子。
The set of epigenetic regulators involved with histone modifications is much larger than the set targeting DNA methylation due to the large number of epigenetic marks that modify histones.参与组蛋白修饰的表观遗传调控因子组远大于靶向DNA甲基化的组，原因是修饰组蛋白的表观遗传标记数量众多。
As such, histone marks are abbreviated by the histone, the modified amino acid and its position, and the epigenetic mark.因此，组蛋白标记由组蛋白、被修饰的氨基酸及其位置以及表观遗传标记缩写表示。
For example, H3K9ac denotes acetylation of the ninth amino acid residue (a lysine or K in standard amino acid abbreviation) of the histone H3 protein.例如，H3K9ac表示组蛋白H3蛋白第九个氨基酸残基（标准氨基酸缩写中的赖氨酸或K）的乙酰化。
Within the two groups of genes (i. e., histone and DNA epigenetic regulators) are so-­ called writers, erasers, and readers of epigenetic marks.在这两类基因（即组蛋白和DNA表观遗传调控因子）中，存在所谓的表观遗传标记的写入者、擦除者和读取者。
Writers place chemical marks on DNA or histones and often carry the term transferase, which connotes this activity.写入者在DNA或组蛋白上放置化学标记，通常带有术语“转移酶”，暗示此活性。
A few examples include the group DNA methyltransferases, histone-­lysine methyltransferases, and histone acetyltransferases.几个例子包括DNA甲基转移酶组、组蛋白-赖氨酸甲基转移酶和组蛋白乙酰转移酶。
Erasers remove chemical marks and include enzyme groups such as histone deactylases and histone demethylases.擦除者移除化学标记，包括酶组如组蛋白去乙酰化酶和组蛋白去甲基化酶。
TET enzymes are the erasers of DNA methylation, for which demethylases are not known to exist.TET酶是DNA甲基化的擦除者，已知不存在针对DNA甲基化的去甲基化酶。
Rather TET proteins initiate a stepwise enzymatic process of methyl group removal that results in demethylation.而是TET蛋白启动一个逐步的甲基基团去除酶促过程，导致去甲基化。
Readers are usually nonenzymatic proteins that bind to specific chemical marks.读取者通常是结合特定化学标记的非酶蛋白。
The fourth and broadest group is remodelers.第四类也是最广泛的一类是重塑者。
These enzymes work within large protein complexes to alter chromatin state/­3D structure, typically at the nucleosome level.这些酶在大型蛋白质复合物中工作，以改变染色质状态/三维结构，通常在核小体水平。
This includes changing the conformation of the nucleosome DNA, the position of the nucleosome along the DNA, or exchanging histone variants within a nucleosome.这包括改变核小体DNA的构象、核小体沿DNA的位置，或交换核小体内的组蛋白变体。
The association between epigenetic regulators and genetic disorders will be discussed later in the chapter.表观遗传调控因子与遗传疾病之间的关联将在本章后面讨论。
Specifically, we will describe a group of mendelian neurodevelopmental disorders caused by pathogenic variants in genes encoding epigenetic regulators.具体而言，我们将描述一组由编码表观遗传调控因子的基因致病性变异引起的孟德尔神经发育障碍。
Histone and DNA modifications function interdependently, with accumulating evidence for temporal and spatial colocalization of certain groups of epigenetic marks, suggesting the likelihood of combinatorial effects.组蛋白和DNA修饰相互依赖，且累积证据表明某些表观遗传标记组存在时间和空间共定位，提示组合效应的可能性。
One example of this interdependency of different modifications is that regions of methylated DNA commonly lack di-­ and trimethylation of histone H3 at lysine 4 (H3K4me 2 and H3K4me 3, respectively).不同修饰相互依赖的一个例子是：甲基化DNA区域通常缺乏组蛋白H3赖氨酸4的二甲基化和三甲基化（分别为H3K4me2和H3K4me3）。
While DNA methylation is associated with transcriptional repression, these histone methylation marks (H3K4me 2 and H3K4me 3) typically occur at transcriptionally active loci.虽然DNA甲基化与转录抑制相关，但这些组蛋白甲基化标记（H3K4me2和H3K4me3）通常出现在转录活性位点。
However, there are many known exceptions to these rules.然而，这些规则有许多已知的例外。
The current hypothesis as to the mutual interdependence of these two marks is that the presence of DNA methylation excludes the histone methyltransferase enzyme from binding and depositing di-­ and trimethyl groups to H3K4.目前关于这两种标记相互依赖的假说认为，DNA甲基化的存在阻止了组蛋白甲基转移酶结合并将二甲基和三甲基基团沉积到H3K4上。
In fact, many enzymes that act to deposit or remove chemical modification to histone tails have protein domains that are sensitive to DNA methylation.事实上，许多作用于组蛋白尾部添加或移除化学修饰的酶具有对DNA甲基化敏感的蛋白质结构域。
For example, SETDB1 and SETDB2 are two epigenetic writers that function as histone-­lysine methyltransferases; both paralogs contain a methyl-­Cp G-­binding domain (MBD), which enables the encoded proteins to localize to methylated DNA in addition to cooperation with other proteins known as binding partners.例如，SETDB1和SETDB2是作为组蛋白-赖氨酸甲基转移酶起作用的两种表观遗传写入者；两个旁系同源物均包含一个甲基CpG结合结构域（MBD），使编码的蛋白能够定位于甲基化DNA，并与称为结合伴侣的其他蛋白质协同作用。
Inversely, other histone-­modifying enzymes can prevent the localization of DNA methylation machineries and protein complexes that lead to chromatin compaction.相反，其他组蛋白修饰酶可阻止导致染色质压缩的DNA甲基化机制和蛋白质复合物的定位。
While we have an incomplete understanding of the crosstalk between DNA and histone modifications, they do not act as isolated units.虽然我们对DNA和组蛋白修饰之间的交互对话了解尚不完全，但它们并非作为孤立单元起作用。
As well, the immense number of possible combinations of various modifications and context sensitivity make for an exceptionally complex regulatory mechanism.同样，各种修饰和上下文敏感性的巨大可能组合构成了极其复杂的调控机制。
EPIGENETICS IN DEVELOPMENT Now that we have discussed how and where epigenetic marks, particularly DNA methylation, exist in the human genome, we will focus on the critical role of epigenetics in human development.发育中的表观遗传学 既然我们已经讨论了表观遗传标记（特别是DNA甲基化）在人类基因组中存在的方式和位置，我们将重点关注表观遗传学在人类发育中的关键作用。
Comprehending how these mechanisms function in development will provide a context for their contributions to pathophysiology of certain diseases and disorders.理解这些机制在发育中如何发挥作用，将为其在特定疾病和障碍病理生理学中的贡献提供背景。
Arguably, one of the most important roles of DNA methylation occurs during embryonic and fetal development, wherein it participates in regulating cell differentiation, conferring a stable cell/­tissue-­specific identity.可以说，DNA甲基化最重要的作用之一发生在胚胎和胎儿发育期间，在此期间它参与调控细胞分化，赋予稳定的细胞/组织特异性身份。
As such, DNA methylation displays tissue-­ and cell-­specific patterns.因此，DNA甲基化显示出组织和细胞特异性模式。
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Principles of Clinical Epigenetics 137 tissue of origin is one of the largest determinants of DNA methylation variation …
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Principles of Clinical Epigenetics 137 tissue of origin is one of the largest determinants of DNA methylation variation in healthy individuals, accounting for greater variation than genetic background.临床表观遗传学原理137 组织来源是健康个体中DNA甲基化变异的最大决定因素之一，其引起的变异比遗传背景更大。
Epigenetic states are most dynamic during germ cell specification and early embryogenesis, two time periods distinguished by epigenetic reprogramming .表观遗传状态在生殖细胞特化和早期胚胎发生期间最为动态，这两个时期以表观遗传重编程为特征。
Our knowledge of these processes comes primarily from studies in mice; however, recent genetic and functional data from human studies have shown that epigenetic reprogramming in the gametes and embryo are generally parallel in humans and mouse, although important differences are being identified that require further investigation.我们对这些过程的了解主要来自小鼠研究；然而，最近来自人类研究的遗传和功能数据表明，配子和胚胎中的表观遗传重编程在人类和小鼠中通常是平行的，尽管正在发现需要进一步研究的重要差异。
During primordial germ cell specification in a fetus at ~5 weeks of gestation there is global erasure of DNA methylation followed by remethylation and imprint acquisition in the differentiating germ cells prior to maturing into oocytes or sperm depending on the sex of the fetus.在约孕5周胎儿的原始生殖细胞特化过程中，发生DNA甲基化的全局擦除，随后在分化中的生殖细胞中重新甲基化并获得印记，之后根据胎儿性别成熟为卵母细胞或精子。
The resulting highly divergent DNA methylation patterns are associated with distinct differentiated/­ transcriptional states.由此产生的高度分化的DNA甲基化模式与不同的分化/转录状态相关。
Together, the DNA and histone modifications, as well as molecules that support 3D DNA structure, constitute the epigenome.DNA和组蛋白修饰以及支持3D DNA结构的分子共同构成表观基因组。
To that end, after fertilization, the chromatin in the zygote is generally open but not transcribed.为此，受精后，合子中的染色质通常是开放的，但不进行转录。
This is followed by rapid remodeling leading to zygotic genome activation at the eight-­cell stage in human embryos.随后发生快速重塑，导致人类胚胎在八细胞期激活合子基因组。
Prior to implantation the embryo undergoes genome-­wide DNA methylation reprogramming.在着床前，胚胎经历全基因组DNA甲基化重编程。
This comprises rapid and enzymatically driven/­active demethylation of the paternal genome.这包括父源基因组的快速且酶驱动的主动去甲基化。
By comparison, demethylation of the maternal genome occurs mainly through passive demethylation over several cell divisions.相比之下，母源基因组的去甲基化主要通过多个细胞分裂中的被动去甲基化发生。
The lowest levels of methylation in the maternal genome occur at the blastocyst stage, at which time the two parental genomes are comparable.母源基因组中甲基化水平最低出现在囊胚阶段，此时两个亲本基因组相当。
Importantly, the imprinted loci are excluded from this stage of reprogramming, and gametic imprinting marks are retained .重要的是，印记位点在此重编程阶段被排除，配子印记标记得以保留。
DNA methylation at these loci is protected from genome-­wide demethylation/­ remethylation in the embryo.这些位点的DNA甲基化免受胚胎中全基因组去甲基化/重新甲基化的影响。
The mechanism, although not yet completely understood, involves protein complexes encoded by maternal effect genes.其机制虽尚未完全阐明，但涉及由母源效应基因编码的蛋白质复合物。
These genes are transcribed from the maternal genome before fertilization, generating transcripts/­proteins required by the early embryo before zygotic genome activation occurs at the eight-­cell stage.这些基因在受精前从母源基因组转录，产生早期胚胎所需的转录本/蛋白质，直至八细胞期发生合子基因组激活。
The majority of maternal effect genes have been studied in mice, including their phenotypic outcomes when dysregulated by a targeted deletion.大多数母源效应基因已在小鼠中研究过，包括靶向缺失导致失调时的表型结果。
Maternal effect genes serve similar functions in humans in that their epigenomic/­organizational role is a requirement for normal developmental competence.母源效应基因在人类中具有类似功能，即其表观基因组/组织作用对于正常发育能力是必需的。
See Genomic Imprinting later for phenotypic outcomes associated with pathogenic variants in these genes.有关这些基因致病性变异相关的表型结果，请参阅后续的“基因组印记”部分。
DNA methylation reprogramming during human development.人类发育过程中的DNA甲基化重编程。
Methylation of imprinting centers (ICs) (dashed black line) is erased more slowly than that of the rest of the genome (black line) in primordial germ cells (PGCs) and reestablished with different kinetics in male (paternal ICs, dashed blue line; whole genome, blue line) and female (maternal ICs, dashed red line; whole genome, red line) germ cells.在原始生殖细胞（PGCs）中，印记中心（ICs）（黑色虚线）的甲基化擦除速度比基因组其余部分（黑色实线）更慢，并在雄性（父源IC，蓝色虚线；全基因组，蓝色实线）和雌性（母源IC，红色虚线；全基因组，红色实线）生殖细胞中以不同的动力学重新建立。
After fertilization, the maternally and paternally derived genomes are widely demethylated, while differential methylation between maternal and paternal IC alleles (50% level) is maintained preimplantation and postimplantation.受精后，母源和父源基因组被广泛去甲基化，而母源和父源IC等位基因之间的差异甲基化（50%水平）在着床前和着床后得以维持。
Factors and events involved in each stage, 5-­methylcytosine level and approximate timing of imprint erasure, establishment and preimplantation and postimplantation maintenance are indicated. g DMRs, Germline differentially methylated regions; GVs, germinal vesicles; SCMC, subcortical maternal complex.指出了每个阶段涉及的因素和事件、5-甲基胞嘧啶水平以及印记擦除、建立和着床前与着床后维持的大致时间。gDMRs，种系差异甲基化区域；GVs，生发泡；SCMC，皮质下母源复合体。
(From Monk D, Mackay DJG, Eggermann T, et al: Genomic imprinting disorders: lessons on how genome, epigenome and environment interact, Nat Rev Genet 20:235–­248, 2019. doi:10. 1038/­s 41576-­018-­0092-­0.) .（摘自 Monk D, Mackay DJG, Eggermann T, 等：基因组印记疾病：关于基因组、表观基因组和环境如何相互作用的启示，Nat Rev Genet 20:235–248, 2019. doi:10.1038/s41576-018-0092-0。）
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Following implantation, parallel remethylation of the maternal and paternal genomes occurs in a cell-­type–­ dependent a…
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Following implantation, parallel remethylation of the maternal and paternal genomes occurs in a cell-­type–­ dependent and time-­dependent manner.植入后，母源和父源基因组以细胞类型依赖性和时间依赖性的方式发生平行再甲基化。
Precursor cells (cells that are not yet terminally differentiated) undergo a stepwise differentiation process in which epigenetics plays a critical role.前体细胞（尚未终末分化的细胞）经历一个逐步分化过程，其中表观遗传学起关键作用。
For example, during differentiation, DNA methylation is required to silence pluripotency factors; the promoters of genes associated with pluripotency, such as Oct 4 and Nanog, are hypermethylated and silenced.例如，在分化过程中，DNA甲基化需要沉默多能性因子；与多能性相关的基因（如Oct4和Nanog）的启动子被高度甲基化并沉默。
As well, DNA methylation acts to upregulate markers associated with germ-­layer specificity.同样，DNA甲基化上调与胚层特异性相关的标志物。
In embryonic stem cells lacking DNA methylation, differentiation is inhibited.在缺乏DNA甲基化的胚胎干细胞中，分化受到抑制。
While some epigenetic processes are thought to drive transcriptional programs based on various inputs, spatial and temporal, other epigenetic changes are believed to enforce these changes and create a barrier that prevents dedifferentiation.虽然一些表观遗传过程被认为基于多种空间和时间输入驱动转录程序，但其他表观遗传变化被认为强化这些变化并形成防止去分化的屏障。
The results of these tightly orchestrated epigenetic patterns are lineage-­ specific transcription profiles that confer cellular identity.这些精巧协调的表观遗传模式的结果是赋予细胞身份的谱系特异性转录谱。
Moreover, these profiles are maintained across cell divisions, as epigenetic patterns are mitotically heritable.此外，这些谱系在细胞分裂中得以维持，因为表观遗传模式是有丝分裂可遗传的。
THE ENVIRONMENT INTERACTS WITH THE EPIGENOME There is a strong interest in epigenetic mechanisms within the developmental origins of health and disease (DOHa D) field.环境与表观基因组相互作用 在健康与疾病的发育起源（DOHaD）领域中，人们对表观遗传机制有着浓厚的兴趣。
The DOHa D paradigm posits that environmental factors during fetal development and infancy contribute to chronic disease susceptibility.DOHaD范式认为，胎儿发育期和婴儿期的环境因素会影响慢性疾病易感性。
The seminal research in this field identified geographic links between low birthweight in the United Kingdom associated with increased fetal mortality, as well as adult cardiovascular disease.该领域的开创性研究确定了英国低出生体重与胎儿死亡率增加以及成人心血管疾病之间的地理关联。
These findings identified poor in utero nutrition and impaired fetal growth as contributing factors to adult cardiovascular disease, initially by observing that regions of England and Wales with the highest rates of coronary heart disease also had increased infant mortality rates in the decades prior.这些发现最初通过观察到英格兰和威尔士冠心病发病率最高的地区在之前几十年中婴儿死亡率也较高，从而确定宫内营养不良和胎儿生长受损是成人心血管疾病的促成因素。
Further work across England and then Europe identified poor prenatal nutrition as an environmental risk for both outcomes, providing strong evidence that prenatal environment contributed to later health outcomes.随后在英国乃至欧洲的进一步工作确定产前营养不良是这两种结局的环境风险因素，为产前环境影响后期健康结局提供了有力证据。
Longitudinal findings from adults exposed in utero to the Dutch Hunger Winter established many long-­ term health outcomes of prenatal starvation, including increased risk of obesity, abnormal lipid profiles, cardiovascular disease, and neuropsychiatric disorders.对宫内暴露于荷兰饥荒的成人的纵向研究结果确立了产前饥饿的许多长期健康结局，包括肥胖风险增加、血脂异常、心血管疾病和神经精神疾病。
These outcomes differ based on the timing of exposure; those exposed only during early gestations had normal birthweights (but increased risk of obesity), while those exposed at later gestations had reduced birthweights.这些结局因暴露时间而异；仅在妊娠早期暴露者出生体重正常（但肥胖风险增加），而在妊娠后期暴露者出生体重降低。
Importantly, these contrasting phenotypes allow us to define critical periods of development (i. e., during development) for a given biologic system where there exists a window of sensitivity during which certain environmental exposures can cause lasting changes.重要的是，这些对比鲜明的表型使我们能够为特定生物系统定义发育关键期（即发育过程中），其中存在一个敏感窗口期，期间某些环境暴露可导致持久改变。
Here long-­term metabolism was altered in response to starvation during early gestation despite the paradoxic healthy birthweights.在此，尽管出生体重异常健康，但早期妊娠饥饿导致长期代谢改变。
By contrast, reduced kidney function was observed more prevalently in individuals exposed during midgestation.相比之下，在妊娠中期暴露的个体中观察到肾功能下降更为普遍。
A continuation of work on this natural experiment also identified corresponding DNA methylation changes, suggesting a role for epigenetics in molecular architecture underlying the physiologic response/­changes.对这一自然实验的后续研究还发现了相应的DNA甲基化变化，表明表观遗传学在生理反应/变化的分子结构中发挥作用。
Notably, insulin-­like growth factor 2 (IGF2), a gene that is critical to prenatal growth and cell proliferation, was found to be hypomethylated (i. e., lower methylation levels that are commonly associated with increased gene activity) in individuals exposed in early gestation, as compared to their unexposed siblings.值得注意的是，与未暴露的同胞相比，早期妊娠暴露的个体中，胰岛素样生长因子2（IGF2）——一个对产前生长和细胞增殖至关重要的基因——被发现低甲基化（即甲基化水平较低，通常与基因活性增加相关）。
By comparison, this difference in IGF2 methylation was not observed in pairs of individuals exposed in late gestation and their siblings.相比之下，在晚期妊娠暴露个体与其同胞中未观察到IGF2甲基化的这种差异。
The Agouti mouse model is also a classic example of how epigenetic mechanisms act as a temporal bridge between in utero exposures and health outcomes in adulthood.刺鼠小鼠模型也是一个经典例子，说明表观遗传机制如何作为宫内暴露与成年期健康结局之间的时间桥梁。
The Agouti gene in mice, which controls fur color via melanin production, is regulated by a cell-­ type–­specific promoter found in the second exon of the gene.小鼠的刺鼠基因通过黑色素产生控制毛色，其调控由该基因第二外显子中的细胞类型特异性启动子介导。
This promoter results in gene activation during hair follicle cell development.该启动子在毛囊细胞发育过程中导致基因激活。
However, the insertion of an intracisternal A-­particle (IAP) retrotransposon in the Agouti gene results in constitutive expression of this gene (i. e., it is expressed in all cells not just hair follicle cells as the retrotransposon contains a cryptic promoter) .然而，在刺鼠基因中插入一个胞内A颗粒（IAP）逆转录转座子导致该基因的组成型表达（即它在所有细胞中表达，而不仅仅是毛囊细胞，因为逆转录转座子含有一个隐蔽启动子）。
This allele is referred to as Avy or the viable yellow allele.该等位基因被称为Avy或活力黄色等位基因。
The phenotype of these mutant mice includes yellow fur, obesity, type II diabetes, and predisposition to tumors.这些突变小鼠的表型包括黄色皮毛、肥胖、Ⅱ型糖尿病和肿瘤易感性。
However, mice with the IAP insertion can have a range of pan-­cellular Agouti expression, and the associated phenotypes are dependent on the levels of DNA methylation at the IAP .然而，携带IAP插入的小鼠可以有一系列的全细胞刺鼠表达，相关表型取决于IAP处的DNA甲基化水平。
Furthermore, a diet rich in methyl donors fed to pregnant Agouti mice can alter the expression of the Agouti gene in the offspring, which will in turn impact long-­ term health.此外，给妊娠期刺鼠小鼠喂食富含甲基供体的饮食可改变后代中刺鼠基因的表达，进而影响长期健康。
Mothers heterozygous for the Avy allele, when crossed with heterozygous males and fed with a diet high in methyl donors, will more frequently produce healthy brown Avy offspring, who carry high levels DNA methylation acting to repress this gene.当Avy等位基因杂合的雌鼠与杂合雄鼠交配并喂食高甲基供体饮食时，会更频繁地产生健康的棕色皮毛Avy后代，这些后代携带高水平的DNA甲基化以抑制该基因。
By comparison, bisphenol A, an endocrine disruptor, when fed to pregnant mice leads to more Avy offspring with yellow coat colors and lower levels of DNA methylation.相比之下，内分泌干扰物双酚A喂养妊娠小鼠会导致更多Avy后代出现黄色皮毛和更低水平的DNA甲基化。
These regions of phenotype-­associated DNA methylation, which also vary by maternal nutrition, constitute differentially methylated regions (DMRs).这些与表型相关的DNA甲基化区域（也因母体营养而异）构成了差异甲基化区域（DMRs）。
The variation in fur color and health outcomes is especially striking when considering that these mice exhibiting a range of fur color and health outcomes are genetically identically individuals.当考虑到这些表现出多种毛色和健康结局的小鼠是基因相同的个体时，毛色和健康结局的变异尤其引人注目。
These examples highlight the environmental influence on epigenetic regulation impacting physiologic outcomes, but also how DNA methylation can act as a biosensor of past in utero environmental factors.这些例子既强调了环境对表观遗传调控的影响进而影响生理结局，也揭示了DNA甲基化如何作为既往宫内环境因素的生物传感器。
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Principles of Clinical Epigenetics 139 Additional evidence that environmental factors can influence the imprinting proce…
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Principles of Clinical Epigenetics 139 Additional evidence that environmental factors can influence the imprinting process derives from assisted reproductive technologies (ART).临床表观遗传学原理139 环境因素可影响印记过程的额外证据来自辅助生殖技术（ART）。
Originally developed in the 1970s ART was developed as a treatment for infertility caused by fallopian tube obstruction.ART最初于20世纪70年代开发，作为治疗输卵管阻塞所致不孕症的手段。
Since then, the indications for ART have grown and include couples at increased risk for genetic disorders as well as diverse causes of female and male subfertility or infertility ART has the potential to disrupt two critical periods of developmental epigenetic reprogramming: oocyte maturation and retention of gametic imprints following fertilization.自那时起，ART的适应症已扩大，包括遗传病风险增加的夫妇以及女性和男性生育力低下或不孕的各种原因。ART有可能扰动发育性表观遗传重编程的两个关键时期：卵母细胞成熟和受精后配子印记的维持。
Ovarian follicular stimulation may activate oocytes that are not yet fully epigenetically reprogramed.卵巢卵泡刺激可能激活尚未完全进行表观遗传重编程的卵母细胞。
In addition, several aspects of ART (in vitro fertilization, intracytoplasmic sperm injection, and freezing of embryos) may deregulate preimplantation epigenetic reprogramming.此外，ART的多个方面（体外受精、卵胞浆内单精子注射和胚胎冷冻）可能扰乱植入前的表观遗传重编程。
Therefore the reports are not surprising of increased risks of adverse pregnancy outcomes: specifically, low birthweight for gestational age, preterm birth, congenital malformations, and increased rate of imprinting disorders, including Beckwith-­Wiedemann, Russell-­Silver, Angelman, and Prader-­Willi syndromes (see Genomic Imprinting, later).因此，关于不良妊娠结局风险增加的报告并不令人意外：具体包括小于胎龄低出生体重、早产、先天畸形，以及印记障碍发生率增加，包括贝克威思-威德曼综合征、罗素-西尔弗综合征、安吉尔曼综合征和普拉德-威利综合征（见后文“基因组印记”）。
The risk for each of these syndromes in individuals conceived using ART is increased several fold over the general population risk (e. g., for Beckwith-­Wiedemann syndrome this would raise the risk from 1/­13,000 to ~1/­2500, although the absolute risk remains low).通过ART受孕的个体患这些综合征中每一种的风险比一般人群风险增加数倍（例如，对于贝克威思-威德曼综合征，风险将从1/13,000升至约1/2500，尽管绝对风险仍然较低）。
In humans, targeted and genome-­wide molecular testing in individuals born following ART has identified DNA methylation alterations not only at a specific locus associated with known clinical entities but also variable dysregulation at multiple imprinted loci, a phenomenon known as multilocus imprinting disorder.在人类中，对ART后出生的个体进行靶向和全基因组分子检测已发现DNA甲基化改变，不仅在与已知临床实体相关的特定基因座，而且在多个印记基因座存在可变失调，这种现象称为多位点印记障碍。
Studies in humans and model organisms have implicated both ART processes (hormone therapy, in vitro culture medium) and primary subfertility issues (oocyte/­sperm quality or pathogenic variants in maternal effect genes) as contributors to aberrant epigenetic programming in this complex developmental time period.对人类和模式生物的研究表明，ART过程（激素治疗、体外培养基）和原发性生育力低下问题（卵母细胞/精子质量或母源效应基因致病性变异）均与这一复杂发育时期的异常表观遗传编程有关。
We explored earlier the important prenatal environments in relation to epigenetic and phenotypic changes; A 5' 5' 3' 2 ectopic wildtype,a Cp GSites 1-9 A A vy 3' IAP PS1A 1A B Yellow Slightly mottled Mottled Heavily mottled Pseudo Agouti The Avy allele contains a contraoriented intracisternal A-­particle insertion within pseudoexon 1A (PS1A) of the Agouti gene.我们先前探讨了与表观遗传和表型变化相关的重要产前环境；A 5' 5' 3' 2 异位野生型，a CpG位点1-9 A A vy 3' IAP PS1A 1A B 黄色 轻微斑驳 斑驳 重度斑驳 伪刺鼠 Agouti基因的Avy等位基因包含一个反向取向的微囊内A颗粒插入在Agouti基因的伪外显子1A（PS1A）中。
A cryptic promoter (short arrowhead labeled “Avy ectopic”) drives constitutive ectopic Agouti expression.一个隐蔽启动子（短箭头标记为“Avy异位”）驱动组成性异位Agouti表达。
Transcription of the Agouti gene normally initiates from a developmentally regulated hair cycle–­specific promoter in exon 2 (short arrowhead labeled “A,a wild type”).Agouti基因的转录通常从外显子2中受发育调控的毛周期特异性启动子起始（短箭头标记为“A,a野生型”）。
(B) Genetically identical offspring heterozygous for the viable yellow allele (Avy/­a) in the Agouti gene representing the five coat color phenotypes, corresponding to different levels of DNA methylation and associated phenotypes, including obesity.(B) 遗传上相同的后代，对Agouti基因中的活黄色等位基因（Avy/a）杂合，表现出五种毛色表型，对应于不同水平的DNA甲基化和相关表型，包括肥胖。
Mice shown are the same sex and age.所示小鼠为相同性别和年龄。
(A, From Dolinoy DC, Huang D, Jirtle RL: Maternal nutrient supplementation counteracts bisphenol A-­induced DNA hypomethylation in early development, Proc Nat Acad Sci 104(32):13056–­13061, 2007. doi:10. 1073/­pnas. 0703739104; B, Jirtle RL: The Agouti mouse: a biosensor for environmental epigenomics studies investigating the developmental origins of health and disease, Epigenomics 6(5):447–­450, 2014. doi:10. 2217/­epi. 14. 58.)(A, 引自Dolinoy DC, Huang D, Jirtle RL: 母体营养补充可抵消双酚A诱导的早期发育DNA低甲基化, Proc Nat Acad Sci 104(32):13056–13061, 2007. doi:10.1073/pnas.0703739104; B, Jirtle RL: 刺鼠小鼠：用于研究发育起源健康与疾病的环境表观基因组学的生物传感器, Epigenomics 6(5):447–450, 2014. doi:10.2217/epi.14.58.)
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however, plasticity does not end at birth.
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however, plasticity does not end at birth.然而，可塑性并非在出生时终止。
Across the lifespan, DNA methylation patterns continue to change in both predictable and seemingly random ways.在整个生命周期中，DNA甲基化模式持续以既可预测又看似随机的方式发生变化。
These ongoing changes to the epigenome can be illustrated by aging and twin studies, respectively.表观基因组持续发生的这些变化可分别通过衰老研究和双生子研究加以说明。
With regard to the predictable nature of epigenetic patterns across the life span, DNA methylation is the most accurate biologic predictor of chronologic age.关于表观遗传模式在整个生命周期中的可预测性，DNA甲基化是生理年龄最准确的生物学预测指标。
For unknown reasons, a small subset of Cp Gs sites acts as a molecular clock.因未知原因，一小部分CpG位点充当分子时钟。
Furthermore, many health behaviors and disease states are associated with an advanced epigenetic clock (i. e., a predicted age older than one’s chronologic age).此外，许多健康行为和疾病状态与表观遗传时钟加快（即预测年龄大于实际年龄）相关。
Significant gaps between the predicted epigenetic age and chronologic age have been associated with increased mortality and morbidity, which may reflect a relationship between DNA methylation and the aging process.预测的表观遗传年龄与实际年龄之间的显著差距与死亡率和发病率升高相关，这可能反映了DNA甲基化与衰老过程之间的联系。
However, this phenomenon is not well understood and currently provides little insight into the molecular mechanisms that underlie the aging process, a situation that will likely be clarified by future research.然而，这一现象尚未被充分理解，目前对衰老过程的分子机制提供的见解甚少，这种情况可能会在未来的研究中得到阐明。
The second example of DNA methylation patterns across the life span is best observed in monozygotic twins, who are born with nonidentical but highly concordant DNA methylation patterns.第二个关于整个生命周期中DNA甲基化模式的例证在同卵双生子中最为明显，他们出生时具有非完全相同但高度一致的DNA甲基化模式。
These relatively small DNA methylation differences observed at birth are likely related to differences experienced in utero despite sharing an embryonic environment.出生时观察到的这些相对较小的DNA甲基化差异，很可能是由于尽管共享胚胎环境，但宫内经历不同所致。
Following birth, the DNA methylation patterns of monozygotic twins become increasingly divergent with age.出生后，同卵双生子的DNA甲基化模式随年龄增长愈发趋异。
This well-­described pattern of diverging DNA methylation patterns across the life spans of twins likely occurs in response to ongoing environmental differences as well as stochastic molecular events such as errors in epigenetic machinery.双生子生命周期中这种被充分描述的DNA甲基化模式趋异现象，很可能是对持续的环境差异以及表观遗传机制错误等随机分子事件的响应。
Importantly, DNA methylation differences in monozygotic twins at all ages have been associated with many discordant phenotypes, including psychiatric disorders (e. g., schizophrenia and bipolar disorder) and autoimmune diseases (e. g., lupus erythematosus and multiple sclerosis).重要的是，同卵双生子在各个年龄段的DNA甲基化差异与许多不一致的表型相关，包括精神疾病（如精神分裂症和双相障碍）以及自身免疫性疾病（如红斑狼疮和多发性硬化）。
This work speaks to plasticity that is mediated by DNA methylation beyond the formative years of fetal development and its role as an interface between one’s environment and health outcomes.这项工作揭示了在胎儿发育关键期之后由DNA甲基化介导的可塑性，以及其作为个体环境与健康结局之间桥梁的作用。
THE ROLE OF EPIGENETICS IN HUMAN DISEASE It was the elegant nuclear transfer experiments in mouse embryos that originally led to the discovery that the mammalian maternal and paternal genomic contributions to the fertilized egg, provided by the haploid germ cells, have different effects on the developing embryo.表观遗传学在人类疾病中的作用 最初正是小鼠胚胎中精巧的核移植实验导致了一项发现：由单倍体生殖细胞提供的哺乳动物母本和父本基因组对受精卵的贡献，对发育中的胚胎具有不同影响。
Zygotes were created carrying either two nuclei of maternal or paternal origin generating exclusively embryonic or placental tissue, respectively, but no viable embryos.创建的合子分别携带两个母源或父源细胞核，从而仅产生胚胎组织或胎盘组织，但未能产生存活胚胎。
Evidence in humans of the functional difference between the maternal and paternal genomes came from studying human germ cell tumors, specifically hydatidiform moles and ovarian teratomas.人类中母本与父本基因组功能差异的证据来自对人类生殖细胞肿瘤的研究，特别是葡萄胎和卵巢畸胎瘤。
Hydatidiform moles are androgenetic in origin (two paternal genomes, no maternal genome), while ovarian teratomas are gynogenetic (two maternal genomes, no paternal genome).葡萄胎起源于雄激素性（两个父本基因组，无母本基因组），而卵巢畸胎瘤为雌核发育（两个母本基因组，无父本基因组）。
The histopathologic phenotype of ovarian teratomas reveals well-­differentiated fetal structures of all three germ layers (ectoderm, mesoderm, endoderm), while the hydatidiform mole contains only extraembryonic trophoblast elements, providing evidence that the maternally and paternally transmitted genomes are not functionally equivalent.卵巢畸胎瘤的组织病理学表型显示所有三个胚层（外胚层、中胚层、内胚层）分化良好的胎儿结构，而葡萄胎仅含有胚外滋养层成分，这证明母本和父本遗传的基因组在功能上并不等同。
We now know that the functional differences between the maternal and paternal genomes are attributed to genomic imprinting.我们现在知道，母本与父本基因组之间的功能差异归因于基因组印记。
CATEGORIES OF EPIGENETIC DISORDERS Genomic Imprinting As discussed in Chapter 6, imprinted genes are expressed from only one parental allele—­that is, although two copies of the gene are present in the cell, only one copy is expressed.表观遗传疾病的分类 基因组印记 如第6章所述，印记基因仅从一个亲本等位基因表达——也就是说，尽管细胞中存在两个基因拷贝，但只有一个拷贝被表达。
Which copy is expressed depends on the parent of origin and is determined by DNA methylation marks.哪个拷贝被表达取决于亲本来源，并由DNA甲基化标记决定。
The allele that is expressed is unmethylated, and the allele that is silenced is methylated.表达的等位基因未被甲基化，而沉默的等位基因被甲基化。
Although only a small percentage of human genes undergo genomic imprinting, many of these genes are critical regulators of growth and development, and therefore disruption of their normal monoallelic expression results in disorders that often impact both intrauterine and postnatal growth and neurodevelopment.尽管只有一小部分人类基因经历基因组印记，但这些基因中有许多是生长和发育的关键调节因子，因此其正常单等位基因表达被破坏会导致疾病，这些疾病通常影响宫内外生长及神经发育。
The majority of imprinted genes are found in clusters, called imprinted domains, in specific chromosome regions (i. e., 15q11-­13 and 11p15).大多数印记基因成簇存在，称为印记结构域，位于特定染色体区域（即15q11-13和11p15）。
Each imprinted domain is controlled by one or more independent imprinting control regions that regulate in cis the expression of target imprinted genes within the domain.每个印记结构域由一个或多个独立的印记控制区控制，这些控制区顺式调控结构域内靶向印记基因的表达。
More than 120 imprinted genes have been identified across the human genome .已在人类基因组中鉴定出超过120个印记基因。
Epigenetic changes that impact imprinting centers (ICs) and result in transcriptional silencing of a gene that is normally active are referred to as epimutations.影响印记中心（IC）并导致通常活跃的基因转录沉默的表观遗传改变被称为表观突变。
The first human disorders recognized to result from genomic imprinting were Prader-­Willi syndrome and Angelman syndrome (see Chapter 6).最早被确认由基因组印记导致的人类疾病是普拉德-威利综合征和安吉尔曼综合征（见第6章）。
These two neurodevelopmental disorders result from the absence of paternally or maternally expressed genes, respectively, in the chromosome 15q11-­13 imprinted region (which contains a cluster of imprinted genes).这两种神经发育疾病分别由染色体15q11-13印记区域（包含一组印记基因）中父本或母本表达基因缺失所致。
One of the characteristics of imprinting disorders is molecular heterogeneity in that there are several different mechanisms, including epigenetic and/­or genetic, that can disrupt gene expression.印记疾病的特征之一是分子异质性，存在多种不同机制（包括表观遗传和/或遗传）可破坏基因表达。
This is seen with both Prader-­Willi and Angelman syndromes, which can occur due to chromosome deletions, uniparental disomy (two copies of a single chromosome from one parent) (see Chapter 6; e., epimutation), and pathogenic sequence variants (UBE3A in Angelman syndrome).这在普拉德-威利综合征和安吉尔曼综合征中均可观察到，这两种疾病可由染色体缺失、单亲二体（来自同一亲本的单条染色体的两个拷贝）（见第6章；例如表观突变）以及致病性序列变异（安吉尔曼综合征中的UBE3A）引起。
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Principles of Clinical Epigenetics 141 Other examples of paired human imprinting disorders are Beckwith-­Wiedemann and R…
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Principles of Clinical Epigenetics 141 Other examples of paired human imprinting disorders are Beckwith-­Wiedemann and Russell-­Silver syndromes, which are two clinically opposite growth disorders that result from dysregulation of imprinted genes in the chromosome 11p15 region.[TL:failed]
Beckwith-­ Wiedemann syndrome is characterized by overgrowth, whereas Russell-­Silver syndrome is characterized by intrauterine growth restriction and postnatal growth deficiency.[TL:failed]
Beckwith-­Wiedemann syndrome is also associated with an increased risk for the development of embryonal tumors.[TL:failed]
The chromosome 11p15 region contains a cluster of imprinted genes that are organized into two distinct imprinted domains, each with its own imprinting control region: the IC1 domain in the telomeric region and the IC2 domain in the centromeric region.[TL:failed]
The IC1 domain contains the IGF2 and H19 genes, and the IC2 domain contains the CDKN1C, KCNQ1, and KCNQ10T1 genes.[TL:failed]
The genes in these regions undergo parent-­of-­origin imprinting such that typically IC1 is methylated on the paternally derived chromosome resulting in IGF2 expression (promotes cell growth and proliferation) and silencing of H19.[TL:failed]
On the maternally derived chromosome IC2 is methylated, resulting in silencing of KCNQ10T1 and expression of KCNQ1 and CDKN1C (negative regulator of cell proliferation).[TL:failed]
Opposite molecular alterations at IC1 and IC2 lead to an imbalance of growth-­promoting and/­or growth-­suppressing genes in this region, either resulting in overgrowth (Beckwith-­Wiedemann) or undergrowth (Russell-­Silver).[TL:failed]
Therefore these conditions are mirror images of each other both clinically and molecularly .[TL:failed]
Sometimes these two conditions can be seen in the same family when the underlying etiology is a chromosome duplication/­deletion that is transmitted through a male versus a female due to parent-­of-­origin–­ specific imprinting of the chromosome 11p15 region .[TL:failed]
The molecular mechanisms that cause these conditions are complex, and similar to the chromosome 15q11-­13-­related disorders include epigenetic and/­or genetic alterations: cytogenetic aberrations, uniparental disomy, loss or gain of methylation at ICs (i. e., epimutation), and pathogenic sequence variants (CDKN1C in Beckwith-­Wiedemann syndrome [Case 6]).[TL:failed]
Whereas imprinting disorders generally result from disturbed methylation in cis at one imprinted locus, there are also reports of individuals with multilocus imprinting disorders (MLID) in which there is aberrant methylation of multiple imprinted loci.[TL:failed]
Individuals with MLID can present with features specific for a single imprinting disorder or overlapping features of multiple imprinting disorders.[TL:failed]
MLID can be observed in children conceived via ART or caused by pathogenic variants in the patient’s genome (e. g., ZFP57), or pathogenic variants in maternal effect genes such as NLRP5 or PAD16, which encode proteins that impact imprinted loci in trans (see Epigenetics in Development, earlier). -TP73 -RNU5D-1 -DIRAS3 LRRTM1NAP1L5- -RHOBTB3 GPR1-AS ZDBF2 Chr 1 Chr 2 Chr 4 Chr 5 Chr 6 *GRB10 is maternally expressed in placenta and paternally expressed in brain -IGF2R, SLC22A3 HYMAI PLAGL1 PHACTR2 AIM1 -LIN28B, -FAM50B -GRB10* CALCR TFPI2 SGCE PEG10 PPP1R9A CPA4 MEST MESTIT1 COPG2IT1 KLF14 Chr 7 Chr 8 Chr 10 Chr 11 Chr 12 Chr 13 Chr 14 Chr 15 Chr 16 -KCNK9 -INPP5F_V2 NLRP2 AXL C19MC ZIM2 Chr 19 Chr 20 PEG3 -DNMT1 PSIMCT-1 L3MBTL BLCAP NNAT, MIMT1 AN01WT1- -DLGAP2 H19 IGF2 IGF2A5 INS KCNQ1 KCNQ10T1 CDKN1C SLC22A18 PHLDA2 -WIF1 DLK1 RTL1 IRAIN- -RB1 UBE3A NPAP1 NDN MKRN3 MAGEL2 #SNURF-SNRPN MEG3 MIR337 -ZNF597 NAA60 MEG8 GS-ALPHA, GNASXL, EXON1A, NESPAS, MIR269, MIR268 NESP, Ideograms were generated using An ideogram of each human chromosome known to have an imprinted gene based on the imprinted gene catalogue ( and Gene Imprint portal ( is shown.[TL:failed]
Imprinted genes are listed on each ideogram if they were designated as imprinted in both of the aforementioned human imprinted gene catalogs.[TL:failed]
Blue genes are paternally expressed, red genes are maternally expressed, black genes have unknown parent-­of-­origin expression, gray genes have parental expression that is isoform dependent.[TL:failed]
Bold genes are implicated in growth, underlined genes play roles in neurodevelopment.[TL:failed]
Genes in italic have no reported function in growth or neurodevelopment.[TL:failed]
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Individual II-­1 has a diagnosis of Beckwith-­Wiedemann syndrome, which is determined to be due to a de novo chromosome …
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Individual II-­1 has a diagnosis of Beckwith-­Wiedemann syndrome, which is determined to be due to a de novo chromosome duplication of chromosome 11p15 encompassing imprinting center 1 (IC1) on her paternally derived chromosome 11.个体II-1被诊断为贝克威斯-威德曼综合征，确定这是由于在她父源染色体11上发生的包含印记中心1（IC1）的11p15区域的新生染色体重复所致。
She therefore has two copies of paternally imprinted genes in this region and one copy of maternally imprinted genes, which leads to relative hypermethylation of IC1.因此，她在此区域有两个父源印记基因拷贝和一个母源印记基因拷贝，导致IC1相对高甲基化。
When she passes this chromosome duplication on to her children, the parental imprints will be erased and replaced with maternal imprints.当她将此染色体重复传递给子女时，亲本印记将被擦除并替换为母源印记。
Therefore her daughter (III-­2) who inherits the chromosome 11p15 duplication will have two copies of maternally imprinted genes in this region and one copy of paternally imprinted genes, which leads to relative hypomethylation of IC1.因此，她遗传了11p15重复的女儿（III-2）在该区域将有两个母源印记基因拷贝和一个父源印记基因拷贝，导致IC1相对低甲基化。
This is associated with Russell-­Silver syndrome.这与罗素-银综合征相关。
Schematic representation of imprinting regulation at imprinting center 1 (IC1) in the chromosome 11p15 region.染色体11p15区域印记中心1（IC1）印记调控的示意图。
The highlighted box (middle) represents normal expression in which IC1 is methylated on the paternally derived chromosome and unmethylated on the maternally derived chromosome, resulting in expression of insulin-­like growth factor 2 (IGF2) only from the paternal allele.突出显示的方框（中间）表示正常表达，其中IC1在父源染色体上甲基化，在母源染色体上未甲基化，导致胰岛素样生长因子2（IGF2）仅从父源等位基因表达。
(Top) Loss of methylation at IC1 on the paternal allele results in silencing of IGF2; suppression of IGF2 results in reduced growth and causes Russell-­Silver syndrome (RSS).（上）父源等位基因IC1甲基化缺失导致IGF2沉默；IGF2受抑制导致生长减缓并引起罗素-银综合征（RSS）。
(Bottom) Gain of methylation at IC1 on the maternal allele results in activation of IGF2, which promotes growth and causes Beckwith-­Wiedemann syndrome (BWS).（下）母源等位基因IC1甲基化获得导致IGF2激活，促进生长并引起贝克威斯-威德曼综合征（BWS）。
Loss and gain of methylation at IC2 (not shown here) can also lead to BWS and RSS.IC2（此处未显示）的甲基化缺失和获得也可导致BWS和RSS。
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Principles of Clinical Epigenetics 143 Pathogenic variants in maternal effect genes cause variable imprint dysregulation…
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Principles of Clinical Epigenetics 143 Pathogenic variants in maternal effect genes cause variable imprint dysregulation at multiple imprinted loci resulting in a broad range of clinical presentations, including infertility and adverse reproductive outcomes such as hydatidiform moles, recurrent miscarriages, and one or more imprinting disorders.临床表观遗传学原理 143 母源效应基因的致病变异导致多个印记位点出现不同程度的印记失调，从而引起广泛的临床表现，包括不孕不育和不良生殖结局，如葡萄胎、复发性流产以及一种或多种印记障碍。
Therefore, when investigating the etiology of MLID where there is a history of infertility and/­or adverse pregnancy outcomes, one must consider testing not only the proband but also the proband ’s mother.因此，在调查存在不孕不育和/或不良妊娠结局病史的多位点印记障碍（MLID）病因时，必须考虑不仅对先证者进行检测，还要对先证者的母亲进行检测。
Another consideration in the differential diagnosis of overlapping features of multiple imprinting disorders in the same individual is genome-­wide paternal isodisomy.在同一患者中对多重印记障碍重叠特征进行鉴别诊断时，另一个需要考虑的因素是全基因组父源单亲二体。
While genome-­wide uniparental paternal disomy is not associated with a viable pregnancy, mosaicism for genome-­wide paternal isodisomy has been reported in several individuals with overlapping features of multiple imprinting disorders; specifically, conditions resulting from uniparental disomy of imprinted chromosome regions (6q24, 11p15, 14q32, 15q11, 20q13).尽管全基因组父源单亲二体与可存活妊娠无关，但已在数名具有多重印记障碍重叠特征的患者中报道了全基因组父源单亲二体的嵌合体；具体而言，这些病症由印记染色体区域（6q24、11p15、14q32、15q11、20q13）的单亲二体所致。
Genome-­ wide paternal uniparental disomy is typically characterized by mosaicism for paternal uniparental and biparental cell lineages.全基因组父源单亲二体通常以父源单亲细胞系和双亲细胞系的嵌合为特征。
Clinical presentation depends on percentage of mosaic cells and location of the uniparental lineage.临床表现取决于嵌合细胞的百分比以及单亲细胞系的位置。
Disorders Involving Unstable Repeat Expansions Epigenetic mechanisms have been shown to play a critical role in the etiology of disorders due to unstable repeat expansions (see Chapter 13).涉及不稳定重复扩增的疾病 表观遗传机制已被证明在不稳定重复扩增所致疾病的病因学中起关键作用（参见第13章）。
This has been well established for fragile X syndrome, where the expansion of the FMR1 CGG repeat to a full mutation triggers a cascade of epigenetic events, including methylation of the FMR1 promotor, which leads to reduced or absent production of the fragile X mental retardation protein (FMRP).这一点已在脆性X综合征中得到充分证实，其中FMR1基因CGG重复序列扩增至全突变会触发一系列表观遗传事件，包括FMR1启动子的甲基化，从而导致脆性X智力障碍蛋白（FMRP）生成减少或缺失。
In males with normal size FMR1 alleles, the FMR1 promotor is unmethylated resulting in an open chromatin conformation that allows access of transcription factors to the FMR1 promoter, leading to transcription of FMRP.在具有正常大小FMR1等位基因的男性中，FMR1启动子未甲基化，从而形成开放的染色质构象，允许转录因子进入FMR1启动子，进而导致FMRP的转录。
The importance of DNA methylation in mediating the expression of FMRP is illustrated by rare cases of males with full FMR1 expansion and normal cognition, in whom the FMR1 promoter has been shown to remain unmethylated.DNA甲基化在调控FMRP表达中的重要性通过一些罕见病例得以说明：这些男性患者具有FMR1全扩增但认知正常，其FMR1启动子被证实保持未甲基化状态。
Many unstable repeat expansion disorders demonstrate anticipation, whereby increased disease severity and decreased age of onset are observed in subsequent generations.许多不稳定重复扩增疾病表现出遗传早现现象，即在后续世代中观察到疾病严重程度增加且发病年龄提前。
The basis of anticipation is the tendency for unstable repeats to undergo expansion when transmitted from parent to child.遗传早现的基础是不稳定重复序列在从亲代向子代传递时倾向于发生扩增。
It has been proposed that epigenetic factors are involved in both disease pathogenesis and repeat instability.已有研究提出表观遗传因素既参与疾病发病机制，也参与重复序列的不稳定性。
For example, congenital myotonic dystrophy (CDM1) is the most severe form of myotonic dystrophy type 1, a neuromuscular disease caused by the expansion of a CTG repeat in the DMPK gene.例如，先天性强直性肌营养不良（CDM1）是1型强直性肌营养不良最严重的形式，这是一种由DMPK基因中CTG重复序列扩增引起的神经肌肉疾病。
CDM1 shows strong genetic anticipation, as well as altered patterns of DNA methylation.CDM1表现出强烈的遗传早现，以及DNA甲基化模式的改变。
Specifically, in individuals with CDM1, cis-­regulatory elements upstream and downstream of the DMPK gene are often aberrantly methylated, thereby altering chromatin structure and gene expression at this locus—­that is, impairment of these regulatory elements can lead to increased repeat instability providing early evidence for epigenetic involvement in genetic anticipation.具体而言，在CDM1患者中，DMPK基因上游和下游的顺式调控元件常出现异常甲基化，从而改变该位点的染色质结构和基因表达——也就是说，这些调控元件的损伤可导致重复序列不稳定性增加，这为遗传早现中表观遗传的参与提供了早期证据。
Disorders of the Epigenetic Machinery Advances in genome sequencing technology have accelerated the discovery of genes involved in mendelian disorders.表观遗传机器疾病 基因组测序技术的进步加速了对孟德尔疾病相关基因的发现。
Over the last decade, an increasing number of mendelian disorders have been recognized to be caused by sequence variants in genes that are important for maintaining normal epigenetic regulation, including writers, erasers, readers, and chromatin remodelers.在过去十年中，越来越多的孟德尔疾病被认为是由对维持正常表观遗传调控至关重要的基因（包括写入器、擦除器、读取器和染色质重塑因子）的序列变异所引起。
Although the majority of these syndromes are caused by loss of function of a single allele (haploinsufficiency) suggesting that these proteins function in a dosage-­ sensitive manner, both autosomal recessive and X-­linked recessive patterns of inheritance are also described.尽管这些综合征大多数由单个等位基因功能丧失（单倍体剂量不足）引起，表明这些蛋白质以剂量敏感的方式发挥作用，但常染色体隐性和X连锁隐性遗传模式也已有报道。
In contrast to classical imprinting disorders that impact imprinted genes in cis, for this group of disorders the epigenetic dysregulation occurs in trans, impacting multiple genomic-­wide targets.与经典印记障碍（顺式影响印记基因）不同，对于这类疾病，表观遗传失调以反式方式发生，影响多个全基因组靶标。
To date, there are over 80 disorders of the epigenetic machinery that have been identified and likely many more yet to be recognized .迄今为止，已鉴定出80多种表观遗传机器疾病，并且可能还有更多尚未被认识。
These disorders are characterized by a wide range of multisystem anomalies, with the two most common phenotypic features observed being intellectual disability and growth dysregulation.这些疾病以广泛的多系统异常为特征，观察到的两个最常见表型特征是智力障碍和生长失调。
Several of these disorders will be discussed later.其中一些疾病将在后文中讨论。
Disorders of the Epigenetic Machinery: DNA Methylation There are a small number of genes that regulate DNA methylation marks in contrast to those that regulate histones; these include writers, readers, and erasers.表观遗传机器疾病：DNA甲基化 与调控组蛋白的基因相比，调控DNA甲基化标记的基因数量较少；这些基因包括写入器、读取器和擦除器。
Pathogenic variants in each of these genes are associated with specific phenotypes.这些基因中的每一个的致病变异都与特定的表型相关。
Heterozygous germline pathogenic loss-­of-­function variants in the DNA methyltransferase DNMT3A (a writer) cause Tatton-­Brown-­Rahman syndrome (TBRS), a nonprogressive neurodevelopmental disorder characterized by increased growth, intellectual disability, and dysmorphic facial features.DNA甲基转移酶DNMT3A（一种写入器）的杂合种系致病性功能丧失变异导致Tatton-Brown-Rahman综合征（TBRS），这是一种非进行性神经发育障碍，以生长过度、智力障碍和面部畸形特征为特点。
While constitutional pathogenic variants in DNMT3A cause TBRS, somatically acquired pathogenic variants in DNMT3A are associated with over 20% of acute myeloid leukemia (AML) cases.尽管DNMT3A的体质性致病变异导致TBRS，但体细胞获得的DNMT3A致病变异与超过20%的急性髓系白血病（AML
Notably the same pathogenic variants have been reported in association with both AML and TBRS; however, AML rarely occurs in individuals with TBRS, emphasizing the requirement for multistep[TL:missing]
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deregulation in cancer.
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deregulation in cancer.癌症中的失调。
Although there is an increased cancer (myeloid neoplasms, including AML) risk above the baseline population risk in individuals with TBRS, this does not meet the threshold for clinical surveillance; therefore cancer screening is not recommended for these individuals.尽管TBRS患者的癌症（髓系肿瘤，包括AML）风险高于基线人群风险，但未达到临床监测的阈值；因此不建议对这些个体进行癌症筛查。
There are other epigenetic regulators associated with mendelian disorders for which somatically acquired pathogenic variants are involved in cancers, including NSD1 and EZH2, which encode two histone methyltransferases (writers).还有其他与孟德尔疾病相关的表观遗传调控因子，其体细胞获得性致病变异涉及癌症，包括编码两种组蛋白甲基转移酶（写入器）的NSD1和EZH2。
Similarly, the phenotypes associated with germline pathogenic variants in these genes (Sotos syndrome and Weaver syndrome, respectively) have an increased cancer risk above the baseline population risk, which does not meet the threshold for clinical surveillance.类似地，这些基因（分别为索托斯综合征和韦弗综合征）的胚系致病变异相关表型，其癌症风险高于基线人群风险，但未达到临床监测的阈值。
Of interest, pathogenic variants in DNMT1, the maintenance methyltransferase, are associated with two distinct progressive adult-­onset neurologic disorders.值得注意的是，维持性甲基转移酶DNMT1的致病变异与两种不同的进行性成年发病神经疾病相关。
These are the only adult-­onset conditions associated with pathogenic variants in an epigenetic regulator that we currently recognize and likely result from the ongoing loss of the cell’s capacity to maintain critical DNA methylation marks.这些是我们目前认识到的与表观遗传调控因子致病变异相关的仅有的成年发病疾病，可能源于细胞持续丧失维持关键DNA甲基化标记的能力。
The specific phenotype is determined by the position of the pathogenic variants in the gene.特定表型由基因中致病变异的位置决定。
Hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (HSAN1E), associated with variants in exon 20, is a disorder that presents in early adulthood with sensory neuropathy and hearing loss and progresses to dementia.与外显子20变异相关的伴痴呆和听力损失的遗传性感觉和自主神经病1型（HSAN1E）是一种疾病，表现为成年早期出现感觉神经病和听力损失，并进展为痴呆。
The second syndrome, associated with variants in exon 21 of DNMT1, is called autosomal dominant cerebellar ataxia, deafness and narcolepsy and is characterized by adult-­onset of narcolepsy followed by the onset of sensorineural deafness, cerebellar ataxia, and ultimately dementia.第二种综合征与DNMT1外显子21的变异相关，称为常染色体显性小脑性共济失调、耳聋和发作性睡病，其特征为成年发病的发作性睡病，随后出现感音神经性耳聋、小脑性共济失调，最终出现痴呆。
Methyl-­Cp G-­binding protein 2 (Me CP2), which functions as a reader of DNA methylation marks, has been studied extensively in part because pathogenic variants in this gene cause a well-­recognized neurodevelopmental disorder, Rett syndrome (Case 40), which is characterized by acquired microcephaly, progressive intellectual disability, and loss of motor skills beginning in the first year of life.甲基-CpG结合蛋白2（MeCP2）作为DNA甲基化标记的读取器，已被广泛研究，部分原因是该基因的致病变异导致一种公认的神经发育障碍——雷特综合征（病例40），其特征为出生后第一年出现获得性小头畸形、进行性智力残疾和运动技能丧失。
The majority (90%) of classic Rett syndrome cases are caused by loss-­of-­function variants in Me CP2, located at Xq 28.大多数（90%）经典雷特综合征病例是由位于Xq28的MeCP2功能丧失性变异引起的。
Those with classic Rett Recessive Recessive Growth Intellectual disability Dominant X-linked abnormalities Autosomal A and Dominant Remodeler, Writer, and Eraser epigenetic enzyme domains that also carry a Reader domain Over 70 genes with defined epigenetic domains (reader, writer, eraser, remodeler, middle icons) have been linked to mendelian phenotypes.那些患有典型雷特综合征的隐性隐性生长智力残疾显性X连锁异常常染色体A和显性重塑酶、写入酶和擦除酶表观遗传酶结构域（也带有读取结构域）超过70个具有明确表观遗传结构域（读取器、写入器、擦除器、重塑酶、中间图标）的基因已与孟德尔表型相关联。
The majority of genes cause disease in the heterozygous state (filled circle).大多数基因在杂合状态下致病（实心圆）。
Enzyme domains (writer, eraser, remodeler) are mutually exclusive in any given factor but many coexist with a reader domain (gray shading).酶结构域（写入器、擦除器、重塑酶）在任何给定因子中互斥，但许多与读取结构域共存（灰色阴影）。
Intellectual disability is seen in the vast majority (blue), as are growth abnormalities (orange).绝大多数（蓝色）出现智力残疾，同样也有生长异常（橙色）。
A = genes on autosomes; X = genes on the X chromosome. :R254–­R264, 2019.)A = 常染色体上的基因；X = X染色体上的基因。:R254–R264, 2019.)
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Principles of Clinical Epigenetics 145 syndrome are generally girls who are heterozygous for the loss-­of-­function vari…
Ch8 — Segment 36
Principles of Clinical Epigenetics 145 syndrome are generally girls who are heterozygous for the loss-­of-­function variants.临床表观遗传学原理 145 综合征通常是杂合有功能丧失变异的女孩。
When boys with a pathogenic Me CP2 variant or deletion survive until birth they exhibit a severe infantile encephalopathy with seizures.当携带致病性 MeCP2 变异或缺失的男孩存活至出生时，他们会表现出伴有癫痫发作的严重婴儿脑病。
As described earlier, the TET family of enzymes acts as erasers of DNA methylation marks.如前所述，TET 酶家族充当 DNA 甲基化标记的擦除器。
Whereas disorders involving writers and readers of DNA methylation have been known for some time, only recently was the first neurodevelopmental disorder impacting the DNA methylation eraser system described.尽管涉及 DNA 甲基化写入器和读取器的疾病已为人所知一段时间，但直到最近才描述了首个影响 DNA 甲基化擦除系统的神经发育障碍。
TET3 deficiency, or Beck-­Fahrner syndrome (BEFAHRS), is caused by either mono-­ and biallelic pathogenic variants in TET3, which encodes methylcytosine dioxygenase and is characterized by highly variable and nonspecific clinical features, including intellectual disability, features of autism, hypotonia, and dysmorphic facial features.TET3 缺乏症，或称 Beck-Fahrner 综合征（BEFAHRS），由 TET3 的单等位或双等位致病性变异引起，TET3 编码甲基胞嘧啶双加氧酶，其特征为高度可变且非特异性的临床特征，包括智力残疾、自闭症特征、肌张力低下和面部畸形。
This syndrome can be transmitted in an autosomal recessive or autosomal dominant manner.该综合征可通过常染色体隐性或常染色体显性方式遗传。
Disorders of the Epigenetic Machinery: Histones The number of genes involved in regulating histone modifications is much larger than for DNA methylation and include writers, erasers, readers, and chromatin remodelers.表观遗传机制障碍：组蛋白 参与调控组蛋白修饰的基因数量远多于 DNA 甲基化，包括写入器、擦除器、读取器和染色质重塑因子。
This group of disorders often presents with overlapping phenotypes, which can make them difficult to differentiate clinically.这类疾病常呈现重叠的表型，使其在临床上难以区分。
This phenotypic overlap can be attributed to the fact that the downstream targets of the various epigenetic regulators, which include different genes, are all involved in the regulation of a common pathway to brain and organ development.这种表型重叠可归因于不同表观遗传调控因子的下游靶点（包括不同基因）均参与调控大脑和器官发育的共同通路。
This means that distinguishing individual disorders is clinically very challenging.这意味着区分单个疾病在临床上极具挑战性。
For example, Sotos and Weaver syndromes are two overgrowth conditions with overlapping features caused by different genes that function as epigenetic writers, NSD1 and EZH2, respectively.例如，Sotos 综合征和 Weaver 综合征是两种过度生长疾病，由功能作为表观遗传写入器的不同基因（分别为 NSD1 和 EZH2）引起，特征重叠。
In spite of the fact that these two genes have different downstream targets, these conditions can be difficult to differentiate clinically especially in the first year or two of life.尽管这两个基因有不同的下游靶点，但这些疾病在临床上难以区分，尤其在生命最初的一两年内。
An accurate clinical diagnosis is important for anticipating the natural history as well as clarifying recurrence risk.准确的临床诊断对于预测自然病程以及明确复发风险至关重要。
Sotos syndrome is associated with significant intellectual and behavioral problems, whereas Weaver syndrome can have relatively mild or no intellectual deficits.Sotos 综合征伴有显著的智力与行为问题，而 Weaver 综合征可能出现相对轻微或无智力缺陷。
There are also differences with respect to the types of cancers and their respective risks in these two conditions, which is important for anticipatory medical care.这两种疾病在癌症类型及其相应风险方面也存在差异，这对预期性医疗照护很重要。
With respect to recurrence risks, most cases of Sotos syndrome have a de novo etiology, whereas Weaver syndrome is often familial, with a milder presentation in a parent only recognized after an affected child is born.关于复发风险，大多数 Sotos 综合征病例为新生病因，而 Weaver 综合征常为家族性，其父母表现较轻微，仅在患儿出生后才被识别。
Phenotypic overlap can also be seen when pathogenic variants occur in genes that function as part of multiprotein complexes.当致病性变异发生在作为多蛋白复合体组成部分的基因中时，也可观察到表型重叠。
In this instance the phenotypic overlap results from the fact that regulation of common downstream targets is disrupted.在此情况下，表型重叠源于共同下游靶点的调控被破坏。
This can be seen in Kabuki syndrome, a neurodevelopmental disorder characterized by growth deficiency, which can be caused by loss of function variants in one of two genes with opposite functions, KMT2D and KDM6A.这在 Kabuki 综合征中可见，这是一种以生长缺陷为特征的神经发育障碍，可由两个功能相反的基因（KMT2D 和 KDM6A）之一的功能丧失变异引起。
KMT2D encodes a histone methyltransferase (writer) and KDM6A encodes a histone demethylase (eraser), two proteins that form a complex and have complementary roles in regulating chromatin state and transcriptional activity at a specific set of target genes.KMT2D 编码组蛋白甲基转移酶（写入器），KDM6A 编码组蛋白去甲基化酶（擦除器），这两种蛋白质形成复合体，在调控特定靶基因组的染色质状态和转录活性中发挥互补作用。
KMT2D adds a methylation mark associated with open chromatin (H3K4me 3), whereas KDM6A removes a mark associated with closed chromatin (H3K27me 3).KMT2D 添加与开放染色质相关的甲基化标记（H3K4me3），而 KDM6A 移除与闭合染色质相关的标记（H3K27me3）。
Both genes facilitate the opening of chromatin and promote gene expression.这两个基因均促进染色质开放并增强基因表达。
Disruption of either gene/­protein function will disrupt the balance of open versus closed chromatin at overlapping target genes resulting in the same clinical outcome (i. e., Kabuki syndrome).任一基因/蛋白质功能的破坏将打破重叠靶基因中开放与闭合染色质的平衡，导致相同的临床结局（即 Kabuki 综合征）。
Identification of the specific genetic etiology is important because pathogenic variants in KMT2D are inherited in an autosomal dominant manner and usually occur de novo, whereas KDM6A is an X-­linked recessive gene that can have a high risk of recurrence if inherited from a phenotypically normal carrier mother.确定特定遗传病因很重要，因为 KMT2D 的致病性变异以常染色体显性方式遗传且通常为新发，而 KDM6A 为 X 连锁隐性基因，若来自表型正常携带者母亲则复发风险较高。
There are also distinct clinical conditions with overlapping phenotypes that are caused by pathogenic variants in different genes within the same multiprotein complex.此外，存在不同临床疾病但表型重叠，由同一多蛋白复合体内不同基因的致病性变异引起。
This can be seen with Coffin-­Siris syndrome (CSS) and Nicolaides-­Baraitser syndrome (NCBRS), two neurodevelopmental disorders that are caused by pathogenic variants in the ARID1B, SMARCB1, and SMARCA4 genes (CSS) and SMARCA2 gene (NCBRS).这可见于 Coffin-Siris 综合征（CSS）和 Nicolaides-Baraitser 综合征（NCBRS），这两种神经发育障碍由 ARID1B、SMARCB1 和 SMARCA4 基因（CSS）以及 SMARCA2 基因（NCBRS）的致病性变异引起。
These genes are all part of the BAF chromatin remodeling complex.这些基因均属于 BAF 染色质重塑复合体。
Although these two conditions have overlapping clinical features, attributable to the common downstream targets of the multiprotein complex that includes the respective causative genes, they also have important differences in natural history that require gene-­based diagnosis for optimal management.尽管这两种疾病具有重叠的临床特征（归因于包含各自致病基因的多蛋白复合体的共同下游靶点），但它们在自然病程上存在重要差异，需要基于基因的诊断以实现最佳管理。
DIAGNOSTIC TESTING FOR EPIGENETIC DISORDERS In light of the fact that the molecular mechanisms that cause imprinting disorders are heterogeneous, one must often utilize more than a single testing methodology to identify the underlying etiology.表观遗传疾病的诊断检测 鉴于导致印记障碍的分子机制具有异质性，通常需采用多种检测方法以确定潜在病因。
The hallmark of imprinting disorders is abnormal DNA methylation patterns.印记障碍的标志是异常的 DNA 甲基化模式。
The most effective first line of investigation for imprinting disorders is methylation-­sensitive multiplex ligation-­dependent probe amplification (MS-­MLPA).印记障碍最有效的一线检测方法是甲基化敏感性多重连接依赖性探针扩增（MS-MLPA）。
See Chapter 5 for a description of the methodology.有关该方法的描述见第 5 章。
The benefit of using MS-­MLPA is that it can assess both methylation levels and copy number variants across the relevant chromosome region; that is, it can distinguish between methylation abnormalities due to a deletion, uniparental disomy, or imprinting defect.使用 MS-MLPA 的优势在于，它可同时评估相关染色体区域的甲基化水平与拷贝数变异；即它能够区分由缺失、单亲二倍体或印记缺陷导致的甲基化异常。
In the case where a methylation abnormality is detected, additional testing may be required to determine the specific underlying molecular etiology.若检测到甲基化异常，可能需要额外检测以确定具体的潜在分子病因。
This could involve这可能涉及
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chromosome microarray analysis to look for a chromosome rearrangement (e. g., deletion not detectable by the targeted probes utilized in MS-­MLPA) or additional molecular testing with parental samples to test for uniparental disomy.染色体微阵列分析用于寻找染色体重排（例如，MS‑MLPA中使用的靶向探针无法检测到的缺失），或使用亲本样本进行额外的分子检测以检测单亲二倍体。
If MS-­MLPA testing is negative, given the underlying molecular heterogeneity in imprinting disorders, additional testing should be considered: specifically, sequence analysis of relevant imprinted genes (i. e., CDKN1C for Beckwith-­Wiedemann syndrome or UBE3A for Angelman syndrome) and cytogenetic analysis for chromosome rearrangements that can impact imprinting without a change in methylation detectable by MS-­MLPA.如果MS‑MLPA检测为阴性，鉴于印记疾病存在潜在的分子异质性，应考虑额外的检测：具体而言，相关印记基因的序列分析（即Beckwith‑Wiedemann综合征的CDKN1C基因或Angelman综合征的UBE3A基因），以及针对可能影响印记的染色体重排的细胞遗传学分析——这些重排不会导致MS‑MLPA可检测到的甲基化改变。
Identification of the etiology is critical to determining recurrence risk.确定病因对于评估复发风险至关重要。
For instance, a de novo methylation abnormality, without a concomitant genetic alteration, would confer a very low recurrence risk, whereas a methylation abnormality due to a deletion at an imprinting control region could confer a 50% risk of recurrence if inherited, depending on parent of origin.例如，无伴随遗传改变的从头甲基化异常将导致极低的复发风险；而由印记控制区缺失引起的甲基化异常，若遗传，则根据亲本来源，复发风险可达50%。
Another consideration in diagnostic testing for imprinting disorders is the fact that the underlying molecular changes may be present in a mosaic state; that is, some cells will have imprinting aberrations and some cells will have appropriate allelic methylation.印记疾病诊断检测中的另一个考虑因素是，潜在的分子改变可能以嵌合状态存在；也就是说，部分细胞存在印记异常，而部分细胞具有合适的等位基因甲基化。
This is commonly seen with chromosome 11p15 molecular alterations that cause Beckwith-Wiedemann syndrome, and accounts for some of the 20% of patients with a clinical diagnosis who have negative results following comprehensive molecular testing.这在导致Beckwith‑Wiedemann综合征的11p15染色体分子改变中常见，并解释了为何20%具有临床诊断的患者在全面分子检测后结果为阴性。
Therefore one must be aware that a negative test result does not exclude a diagnosis because of the significant rate of somatic mosaicism.因此必须注意，由于体细胞嵌合现象的发生率较高，阴性检测结果并不能排除诊断。
Mendelian disorders of the epigenetic machinery have traditionally been diagnosed via genome sequencing, including targeted single gene or panel testing (if a specific diagnosis is suspected) or genome-­wide sequencing.表观遗传机制的孟德尔疾病传统上通过基因组测序来诊断，包括靶向单基因或基因组合检测（若怀疑特定诊断）或全基因组测序。
However, sequencing technologies have several limitations, including coverage of noncoding regions, detection of complex sequence variants, and identification of variants of uncertain significance.然而，测序技术存在若干局限性，包括非编码区域的覆盖、复杂序列变异的检测以及意义不明变异的识别。
A promising approach to improving the diagnostic yield of genetic disorders resulting from pathogenic sequence variants in epigenetic regulators involves analysis of genome-­ wide DNA methylation patterns.提高因表观遗传调控因子致病性序列变异所致遗传疾病诊断率的一种有前景的方法，是分析全基因组DNA甲基化模式。
In the last few years, unique patterns of DNA methylation alterations, called DNA methylation signatures, have been defined for over 50 different genes.在过去几年中，已为超过50种不同的基因定义了独特的DNA甲基化改变模式，称为DNA甲基化特征。
These signatures are developed by comparing peripheral blood–­derived DNA for groups of cases with pathogenic variants in a specific gene to controls.这些特征是通过将特定基因存在致病性变异的病例组与对照组的外周血来源DNA进行比较而得出的。
The utility of these gene-­specific signatures as functional biomarkers for diagnostic testing is increasingly being recognized as a novel tool.这些基因特异性特征作为功能性生物标志物用于诊断检测的实用性，正日益被认可为一种新型工具。
These signatures can be used to classify sequence variants of uncertain significance, as either pathogenic or benign, by comparing a DNA methylation profile generated for a specific case to the genome-­wide DNA methylation signature for the gene in question and to controls.这些特征可用于将意义不明的序列变异分类为致病性或良性，方法是将特定病例生成的DNA甲基化谱与所关注基因的全基因组DNA甲基化特征及对照进行比较。
Given that the DNA methylation signatures to date have been derived in DNA from whole blood and that DNA methylation marks have cell-­type specificity, the current signatures are limited to testing in blood-­derived DNA samples.鉴于迄今为止的DNA甲基化特征均源自全血DNA，且DNA甲基化标记具有细胞类型特异性，当前特征仅限于对血液来源DNA样本进行检测。
In the future as DNA methylation signatures are identified in other cell types, this technology can be more broadly applied.未来，当在其他细胞类型中鉴定出DNA甲基化特征时，该技术可得到更广泛的应用。
DNA METHYLATION AND CANCER DIAGNOSTICS Cancer, although conventionally considered a genetic disorder, often involves genome-­wide epigenetic dysregulation, including alterations to DNA methylation, histone modifications, chromatin remodeling, and micro RNA.DNA甲基化与癌症诊断 癌症虽传统上被视为一种遗传性疾病，但常涉及全基因组表观遗传失调，包括DNA甲基化、组蛋白修饰、染色质重塑和微小RNA的改变。
Given that one important function of eukaryotic DNA methylation is to maintain genomic stability by regulating the expression of oncogenes and tumor suppressor genes, it is not surprising that epigenetic dysregulation often contributes to tumor development and progression.鉴于真核生物DNA甲基化的重要功能之一是通过调节癌基因和肿瘤抑制基因的表达来维持基因组稳定性，因此表观遗传失调常促进肿瘤的发生和发展也就不足为奇了。
Some of this epigenetic dysregulation is driven by somatically acquired pathogenic variants in specific chromatin modifier genes.部分此类表观遗传失调由特定染色质修饰基因中体细胞获得的致病性变异驱动。
Such variants are frequently observed in malignant cells and can result in aberrant genome-­wide methylation changes leading to inappropriately expressed or repressed genes.此类变异在恶性细胞中常见，并可导致全基因组甲基化的异常改变，进而引起基因的异常表达或抑制。
Pathogenic variants in certain epigenetic regulators are often a hallmark of specific tumor types.某些表观遗传调控因子的致病性变异通常是特定肿瘤类型的标志。
DNA methylation patterns are becoming increasingly recognized as valuable diagnostic and prognostic tools in the cancer realm, particularly with respect to their utility in defining specific tumor types.DNA甲基化模式在癌症领域中正日益被认可为有价值的诊断和预后工具，特别是在定义特定肿瘤类型方面具有实用性。
This is especially important in tumors that escape definition by other molecular and pathologic methods.这对于那些通过其他分子和病理方法无法定义的肿瘤尤为重要。
One particularly difficult challenge that can be addressed by DNA methylation is a cancer of unknown origin (i. e., metastatic disease for which the primary tumor is unknown) because the DNA methylation state of cell type at the time of tumor initiation remains identifiable during tumor development and progression.DNA甲基化可以解决的一个特别困难的挑战是来源不明的癌症（即原发肿瘤未知的转移性疾病），因为在肿瘤发生和进展过程中，肿瘤起始时细胞类型的DNA甲基化状态仍可识别。
Therefore the DNA methylation profile of a tumor provides not only data about the current state of the cancer epigenome but also defines the tumor’s cell type of origin.因此，肿瘤的DNA甲基化谱不仅提供了癌症表观基因组的当前状态数据，还确定了肿瘤的起源细胞类型。
As a result, DNA methylation-­based clinical diagnosis and prognosis across many different types of primary cancers are now utilized to predict the primary site of metastatic cancers of unknown primaries.因此，基于DNA甲基化的临床诊断和预后现已用于多种原发癌类型，以预测未知原发性转移癌的原发部位。
In addition to aiding in the diagnosis of tumor origin, DNA methylation-­based diagnostics have been shown to play a valuable role in classifying different tumor subtypes, which can be critical in optimizing treatment/­ management.除了辅助诊断肿瘤起源外，基于DNA甲基化的诊断已被证明在区分不同肿瘤亚型方面具有重要价值——这对于优化治疗/管理可能至关重要。
One example is the ability to classify tissue samples into one of over 80 central nervous system tumors, and (even more valuable) the ability to identify subgroups within a particular tumor type.一个例子是能够将组织样本归类为80多种中枢神经系统肿瘤中的一种，并且（更有价值的是）能够识别特定肿瘤类型内的亚群。
This can be seen in the case of medulloblastomas, where DNA methylation signatures have enabled the subclassification so这可见于髓母细胞瘤病例，其中DNA甲基化特征已实现亚分类，从而使
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Principles of Clinical Epigenetics 147 that four different subtypes are now recognized; these subtypes are associated with dramatic prognostic and therapeutic differences.临床表观遗传学原理147指出，目前公认有四种不同的亚型；这些亚型与显著的预后和治疗差异相关。
We expect that ongoing advances in DNA methylation-­based diagnostics in cancer will be integrated to improve the broader landscape of cancer diagnostics and treatment for patients.我们期待，基于DNA甲基化的癌症诊断技术的持续进展将被整合，以改善癌症诊断和治疗的更广阔前景，造福患者。
TREATMENT FOR NEURODEVELOPMENTAL DISORDERS CAUSED BY PATHOGENIC VARIANTS IN EPIGENETIC REGULATORS Historically postnatal treatment of neurodevelopmental disorders was not considered feasible because prior to our understanding of neuroplasticity the brain was considered to be a fully developed organ early in life.对于由表观遗传调控因子致病性变异引起的神经发育障碍的治疗，历史上出生后治疗被认为不可行，因为在对神经可塑性有认识之前，大脑被认为在生命早期就已完全发育。
Early evidence for possible postnatal treatment of neurodevelopmental disorders came from studies of a mouse model of Rett syndrome, in which the restoration of Mecp 2 function led to reversal of advanced neurologic symptoms in adult mice.出生后治疗神经发育障碍可能性的早期证据来自对Rett综合征小鼠模型的研究，在该模型中，恢复Mecp2功能可逆转成年小鼠晚期神经症状。
Given that a large group of neurodevelopmental disorders result from epigenetic dysregulation and that epigenetic changes are considered reversible, epigenetic mechanisms represent an attractive target for therapeutic intervention.鉴于大量神经发育障碍由表观遗传失调引起，且表观遗传改变被认为是可逆的，表观遗传机制成为治疗干预的一个有吸引力的靶点。
Evidence of the efficacy of drugs that target epigenetic dysregulation was initially noted in clinical trials for cancer.靶向表观遗传失调的药物疗效的证据最初在癌症临床试验中被注意到。
Building on this approach, epigenetic therapeutics were trialed in mouse models of two neurodevelopmental disorders, specifically Rubinstein-­Taybi syndrome (RTS) and Kabuki syndrome (KS), resulting from pathogenic variants in the epigenetic regulators CREB-­binding protein (CREBBP) and KMT2D, respectively.基于这一方法，表观遗传疗法在两种神经发育障碍的小鼠模型中进行了试验，即分别由表观遗传调控因子CREB结合蛋白（CREBBP）和KMT2D致病性变异引起的Rubinstein-Taybi综合征（RTS）和Kabuki综合征（KS）。
In the mouse model of RTS, haploinsufficiency of CREBBP results in deficit chromatin acetylation as well as intellectual and memory deficits.在RTS小鼠模型中，CREBBP单倍剂量不足导致染色质乙酰化缺陷以及智力和记忆缺陷。
Treatment using inhibition of histone deacetylase (HDAC) activity ameliorates both the chromatin acetylation and the memory deficit.使用组蛋白去乙酰化酶（HDAC）活性抑制剂的治疗可改善染色质乙酰化和记忆缺陷。
In the case of KS, pathogenic variants in KMT2D cause a closed chromatin state impeding the transcription of genes critical for normal neurodevelopment.在KS病例中，KMT2D致病性变异导致染色质关闭状态，阻碍对正常神经发育至关重要的基因的转录。
Treatment of KS mice with HDAC inhibitors restores the normal open chromatin state at these targets, resulting in improvement of long-­term memory deficits.用HDAC抑制剂治疗KS小鼠可恢复这些靶点的正常开放染色质状态，从而改善长期记忆缺陷。
In addition, in a mouse model of KS, treatment with a ketogenic diet (which increases β-­hydroxybutyrate levels) was noted to have a similar therapeutic effect.此外，在KS小鼠模型中，生酮饮食（可增加β-羟基丁酸水平）治疗被观察到具有类似治疗作用。
This positive outcome was attributed primarily to the HDAC inhibitor properties of β-­hydroxybutyrate.这一积极结果主要归因于β-羟基丁酸的HDAC抑制特性。
These two models provide further evidence of the potential utility of epigenetic drugs or epigenetic-­based therapies in treating neurodevelopment disorders postnatally.这两个模型进一步证明了表观遗传药物或基于表观遗传的疗法在出生后治疗神经发育障碍方面的潜在效用。
As of the writing of this chapter, some human clinical trials are being developed to evaluate the impact of epigenetic treatment approaches in neurodevelopmental disorders.截至本章写作时，一些人体临床试验正在开展，以评估表观遗传治疗方法对神经发育障碍的影响。
There is a broad range of potential treatment options for neurodevelopmental disorders (see Chapter 14), including approaches that show promise other than epigenetic drugs.神经发育障碍有广泛的潜在治疗选择（见第14章），包括除表观遗传药物外显示出前景的方法。
For example, the use of trofinetide, an IGF analog initially studied in mouse models, has now been shown to reduce repetitive behaviors and seizures in females with Rett syndrome (Case 40).例如，曲非奈肽（trofinetide），一种最初在小鼠模型中研究的IGF类似物，现已被证明可减少Rett综合征女性的重复行为和癫痫发作（病例40）。
Clinical trials are ongoing.临床试验正在进行中。
Although these data are very promising, there remain many potential challenges that need to be addressed.尽管这些数据非常有前景，但仍有许多潜在挑战需要解决。
One of particular importance is to define the critical brain regions that harbor cells that can be modulated postnatally.其中一个特别重要的是确定包含可在出生后调节的细胞的关键脑区。
In this regard, studies in mouse models of both KS and RTS suggest that hippocampal cells in the dentate gyrus have self-­renewal properties that could be channeled into partially rescuing memory and learning deficits in neurodevelopmental disorders.在这方面，对KS和RTS小鼠模型的研究表明，齿状回中的海马细胞具有自我更新特性，可用于部分挽救神经发育障碍中的记忆和学习缺陷。
Other questions to be addressed include navigating the blood-­brain barrier and windows of opportunity for successful treatment.其他需要解决的问题包括穿越血脑屏障以及成功治疗的机会窗口。
Furthermore, current epigenetic agents do not target loci with aberrant epigenetic patterns but alter the epigenetic status at many sites across the genome, which may be associated with a number of adverse effects in unrelated cell types and pathways.此外，目前的表观遗传药物并不靶向具有异常表观遗传模式的基因座，而是改变基因组许多位点的表观遗传状态，这可能与无关细胞类型和通路中的若干不良反应相关。
Future progress in addressing these challenges is required to enable effective treatments of neurodevelopmental disorders.需要在解决这些挑战方面取得未来进展，以实现对神经发育障碍的有效治疗。
FUTURE DIRECTIONS In this chapter we have introduced many different facets of epigenetics and their relative applications, and a number of important themes clearly arise.未来方向 在本章中，我们介绍了表观遗传学的许多不同方面及其相关应用，并且明显出现了一些重要主题。
Foremost, there is mounting evidence pointing to a role for epigenetic changes in health risk and disease in response to both genetic variation and environmental or lifestyle influences.首先，越来越多的证据表明表观遗传改变在健康风险和疾病中发挥作用，以响应遗传变异以及环境或生活方式的影响。
Such epigenetic patterns have been shown to play a role not only in mendelian disorders but also in complex diseases and health outcomes that arise from certain environmental exposures.此类表观遗传模式已被证明不仅在孟德尔疾病中发挥作用，而且在由特定环境暴露引起的复杂疾病和健康结果中也有作用。
The dynamic and reversible nature of epigenetic changes permits a level of adaptability or plasticity that greatly exceeds the capacity of DNA sequence alone and thus is relevant both to the origins and the potential treatment of disease.表观遗传改变的动态和可逆性允许一定程度的适应性或可塑性，这远远超过单独的DNA序列的能力，因此与疾病的起源和潜在治疗都相关。
Current obstacles to fully understanding the role of epigenetic aberrations in disease pathophysiology include (1) the sheer complexity of the epigenome, which consists of many interrelated and context-dependent chemical marks; (2) a unique epigenome that exists for each cell type and changes across the life span, especially during development; and (3) baseline levels of stochastic and nonstochastic variation among individuals, similar to that in the human genome.当前充分理解表观遗传异常在疾病病理生理学中作用的障碍包括：（1）表观基因组的极端复杂性，它由许多相互关联且依赖于环境的化学标记组成；（2）每种细胞类型存在独特的表观基因组，并在整个生命周期中发生变化，尤其是在发育期间；（3）个体之间随机和非随机变异的基线水平，类似于人类基因组中的变异。
A number of large-­scale epigenomics projects (akin to the original Human Genome Project) have been initiated to catalogue DNA methylation sites genome-­wide (the so-­called methylome), to evaluate Cp G landscapes across the genome, to discover new histone variants and modification patterns in various tissues, and to document positioning of nucleosomes多项大规模表观基因组学项目（类似于最初的人类基因组计划）已启动，以编目全基因组DNA甲基化位点（所谓的甲基化组），评估全基因组CpG景观，发现各种组织中的新组蛋白变体和修饰模式，并记录核小体定位。
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around the genome in different cell types and in samples from both healthy individuals and those with cancer or other di…
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around the genome in different cell types and in samples from both healthy individuals and those with cancer or other diseases.在不同细胞类型以及来自健康个体和癌症或其他疾病患者的样本中，基因组范围内的表观遗传模式。
These analyses are part of a broad effort (called the ENCODE Project [Encyclopedia of DNA Elements]) to explore epigenetic patterns in chromatin genome-­wide in order to better understand control of gene expression in different tissues or disease states.[TL:missing]
The data from such efforts can then be channeled into refining our understanding of the role of epigenetics in human health and disease and as a platform for improving personalized medicine approaches to diagnostics and therapeutics.[TL:missing]
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Lanni S, Pearson CE: Molecular genetics of congenital myotonic dystrophy, Neurobiol Dis 132:104533, 2019. nbd. 2019. 104533 Moran S, Martinez-­Cardus A, Sayols S, et al: Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis, Lancet Oncol 17(10):1386–­1395, 2016. org/­10. 1016/­S1470-­2045(16)30297-­2 PROBLEMS 1. a. When in human fetal development does genome-­wide epigenetic reprogramming occur? b.[TL:missing]
How does this type of reprogramming differ by parent of origin?[TL:missing]
Genetically identical Agouti mice heterozygous for the Avy or the viable yellow allele can display a range of phenotypes, including obesity and coat color differences.[TL:missing]
Describe the underlying epigenetic changes associated with expression of the Agouti gene and nutritional manipulations that can alter phenotypic presentation.[TL:missing]
Assisted reproductive technologies (ART) increase the risk of a specific group of epigenetic disorders.[TL:missing]
Name this group of disorders, as well as two specific disorders within this category.[TL:missing]
Mendelian disorders of the epigenetic machinery are characterized by a wide range of multisystem anomalies; however, these diverse disorders share some phenotypic features. a.[TL:missing]
List two common clinical features that are often observed. b.[TL:missing]
Describe two epigenetic functions of the proteins encoded by genes that cause such disorders when they carry pathogenic variants.[TL:missing]
What is a DNA methylation signature?[TL:missing]
What is its application in clinical diagnostics for constitutional disorders of the epigenetic machinery and in the field of oncology?[TL:missing]
Name a drug with an epigenetic mode of action.[TL:missing]