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| General Principles of Medical Genetics |
医学遗传学的一般原则概述 |
| Human development depends on genetic and environmental factors. A person's genetic composition （genome） is established at conception. The genetic information is carried in the DNA of the chromosomes and mitochondria. Most diseases probably have some genetic component, the extent of which varies. Environmental factors may alter genetic information through mutation or other structural alteration and can affect classic genetic disorders （eg, dietary management in phenylketonuria, drugs for hypercholesterolemia）. |
人体发育取决于遗传和环境因素. 一个人的遗传组成（基因组）是在受孕时确立的.遗传信息由染色体和线粒体的DNA携带.大部分疾病程度不同地带有遗传成分.环境因素可以通过诱发突变或其他的结构改变而使遗传信息发生变化并可影响一些经典的遗传性疾病（如苯丙酮尿症的饮食管制,高胆固醇血症的药物治疗）. |
| DNA's capacity to replicate constitutes the basis of hereditary transmission. DNA also provides the genetic code, which determines cell development and metabolism by controlling RNA synthesis. The sequence of the elements （nucleotides） that comprise DNA and RNA determines protein composition and thus its function. |
DNA的复制能力是遗传传递的基础.DNA也提供遗传密码,通过对RNA合成的控制而决定细胞发育和代谢.构成DNA和RNA的基本单位（核苷酸）的顺序决定蛋白质的组成及其功能. |
| Genes （between 60,000 and 100,000 in humans） are carried by the chromosomes （rodlike structures in the cell nuclei） and mitochondria （circular structures in cell cytoplasm present in multiple copies）. In humans, somatic （nongerm） cells normally have 46 chromosomes, occurring as 23 pairs. Each pair consists of one chromosome from the mother and one from the father. One pair, the sex chromosomes, determines a person's sex. Women have two X chromosomes in every somatic cell nucleus, whereas men have one X and one Y chromosome （ie, heterologous chromosomes）. The X chromosome carries genes responsible for many hereditary traits, whereas the small, differently shaped Y chromosome carries the genes that initiate male sex determination. The remaining 22 chromosome pairs, the autosomes, are usually homologous （ie, identical in size, shape, and position and number of genes）. Germ cells （egg and sperm） undergo meiosis, which reduces the number of chromosomes to 23--half that of somatic cells （46）--so that when an egg is fertilized by a sperm at conception, the normal number of chromosomes is reconstituted. In meiosis, the genetic information inherited from a person's mother and father is recombined through crossing over or exchange between the homologous chromosomes. |
基因（人类有6万~10万条）由染色体（细胞核中的杆状结构）和线粒体（存在于细胞质中的多个环形结构）携带.人类中,正常的体细胞（非生殖细胞）有46条染色体,分为23对.每对染色体中,一条来自父亲,一条来自母亲.有一对染色体叫性染色体,决定着人的性别.女性在每个体细胞核中有两条X染色体,男性则有一条X染色体和一条Y染色体（即异源染色体）.X染色体携带着许多遗传特征的基因,而小的,形状不同的Y染色体则携带着决定男性性别的基因.其余的22对染色体叫常染色体,通常是同源的（即染色体的大小,形状和基因的位置,数目一样）.生殖细胞（卵和精子）进行成熟分裂时,染色体数目减为23,是体细胞中 （46）的一半.当卵被精子授精而怀孕时,染色体数又恢复正常.在成熟分裂时,在同源染色体之间可通过交换来重组来自于父亲和母亲的遗传信息. |
| Genes, the basic units of heredity, are arranged linearly within the DNA along the chromosomes; each gene has a specific location （locus） or position on the chromosomes. The number and arrangement of loci on homologous chromosomes are usually identical. However, the structure of a specific gene may have minor variations （polymorphisms） without causing disease. The specific nucleotide sequence of the genes that occupy the two homologous loci along the two chromosomes of a pair are called alleles. The two alleles （ie, the one inherited from the mother and the one inherited from the father） may have slightly different nucleotide sequences or may be the same. A person with a pair of identical alleles for a particular gene is a homozygote; a person with a pair of dissimilar alleles is a heterozygote. |
遗传的基本单位基因是沿着染色体在DNA 分子中呈线状排列的.每一个基因在染色体上有其特定的位置,叫位点.在同源染色体上,位点的数目和排列通常是一样的.然而,某一特定基因可有轻微的结构变化（称为多形性）而不造成疾病.在同一对的两条染色体上占据两个等同位点的核苷酸序列称为等位基因.两个等位基因（一个来自父亲,另一个来自母亲）可有相同的或略有不同的核苷酸序列.一个人如果带有某个基因的两个相同的等位基因,是纯合子；如带有两个不相同的等位基因,则为杂合子.
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| If a trait or disorder occurs when only one allele is abnormal, the disorder is said to be dominant. A disorder is said to be recessive if it occurs only when both alleles at the loci on both chromosomes are abnormal. A few genes are located in the mitochondrial DNA （see below）. Many copies of mitochondrial DNA are present in cytoplasm and may have the same DNA structure （homoplasmy） or different structures （heteroplasmy）. |
如果某一特征或疾病,在仅有一个等位基因异常时就出现,称为显性的,如果要在两个染色体的位点上两个等位基因都异常才出现,则称为隐性的.有几个基因位于线粒体DNA中（见下文）.细胞质中有许多线粒体DNA的拷贝,它们的DNA结构可相同（同质性）,或不同（异质性）. |
| There are three types of genetic disorders: Mendelian, or single-gene, mutations are inherited in recognizable patterns; multifactorial conditions involve > 1 gene and environmental factors interacting in ways that are not always clearly recognizable but that have been described by observation （empirically）; and chromosomal abnormalities include structural defects and deviations from the normal number. More recently, mitochondrial and nontraditional patterns of inheritance have been recognized. |
遗传性疾病分三类：孟德尔遗传,或单基因突变,其遗传方式已知晓；多因子遗传,涉及一个以上的基因及环境因素,其相互作用方式并不总是很明了,但可通过观察（经验地）被描述；染色体异常,包括结构缺陷和偏离正常数目.最近对线粒体和非传统的遗传方式已有所了解. |
| Humans vary phenotypically and genotypically. Heterogeneity results from different alleles and mutations of the multiple genes, which are part of almost all biochemical pathways. Mutations in different parts of a gene may cause different disorders. For instance, mutations in different locations along the gene for one type of collagen can produce tall stature, arthritis, and deafness or lethal dwarfism. More than 60 specific causes of congenital deafness have been identified; some are genetic （involving nuclear and mitochondrial genes）, whereas others result from rubella virus or other environmental agents. Concern about the teratogenic effects of drugs taken during pregnancy is growing. For instance, women who consume alcohol during pregnancy are at increased risk of having infants with mental retardation and behavioral disturbances, intrauterine growth retardation, and congenital malformations. |
各人之间在表型和基因型上可有不同. 这种不均一性源自于不同的等位基因和众多基因的突变,它们参与几乎所有的生化途径.一个基因中不同部位的突变可造成不同的疾病.例如决定某一类型胶原的基因上不同部位的突变可导致身材高大,关节炎和耳聋或致死性侏儒症.现在已知先天性耳聋有60多种病因,有的是遗传性（包括细胞核和线粒体基因）,有的则由风疹病毒或其他环境因子造成.妊娠期间用药的致畸胎作用越来越受到关注.例如孕妇饮酒会增加子女发生智力迟缓和行为障碍,宫内生长迟缓和先天性畸形的危险. |
| Thus, phenotypically similar conditions may be due to mutations in different genes, nongenetic factors, or both. To establish the cause of the person's problem and best determine the risk to future offspring, the physician must take a thorough family history and inquire about possible environmental factors, keeping heterogeneity in mind. Identifying the specific causative agent is not always possible. |
因此表型相似可因不同基因的突变和/或非遗传因子所造成.要确定病人问题的原因和后代的风险,医生必须详细了解其家族史和调查可能的环境因素,要想到不均一性.要鉴定特异的病因并不总是可能的. |
| Powerful molecular genetic techniques have made it possible to study the structure of DNA and to track changes during development and in different tissues. The structure of a gene is complex and includes control elements （eg, promoters, enhancers）, expressed elements （exons）, intervening elements that are not expressed （introns）, and a termination signal. The configuration of the DNA of a gene in a tissue that does not express the gene is likely to be different （eg, methylated, condensed） than that of a gene that is actively expressing. |
强大的分子遗传学技术已可能研究DNA的结构,追踪发育阶段不同组织中的变化.基因的结构是复杂的,还包括控制成分（如启动子,增强子）,表达成分（外显子）,不表达的插入成分（内含子）和一个终止信号.在组织中不表达的基因的DNA构型和表达活跃时相比很可能是不同的（如乙基化,浓缩化）. |
| The human genome project is a large collaborative international project that began in 1991. The goal is to map specific genes to specific locations on chromosomes and determine their exact nucleotide sequence （the genome of a human） by 2005. Mapping can be done through family studies, using the known location of DNA markers, and involves isolating small stretches of DNA and sequencing the genes and the other DNA in that area. |
人类基因组计划是1991年开始的规模巨大的国际合作项目.它的目标是到2005年把特异的基因画到染色体的特定位置上并测定其确切的核苷酸序列（人的基因组）.基因画图可以利用DNA标记的已知位置通过家系研究进行,并包括分离小的DNA延伸和测定基因和该区域中其他DNA的序列.
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| Genetic Screening Genetic screening may be used in populations at risk for a particular genetic disorder. Genetic screening is only appropriate when the natural history of the disease is understood; the screening tests are valid and reliable; sensitivity, specificity, false-negative, and false-positive rates are acceptable; and effective therapy is available. A sufficient benefit must be derived from a screening program to justify its cost. |
遗传筛查 遗传筛查可用于易患人群检测特定遗传病.遗传筛查只有在该遗传病的自然史已被了解的情况下才有用.这时,筛查试验是有效的,可信的,其敏感性,特异性,假阴性率和假阳性率都是可接受的,并可进行有效治疗.从筛查计划中必须产生足够的效益以证明其费用开支是值得的. |
| Heterozygote screening: Screening a susceptible population （eg, Tay-Sachs disease in Ashkenazic Jews, sickle cell anemia in blacks, thalassemia in various ethnic groups） may be appropriate because of the high frequency of heterozygotes. Heterozygote screening can determine if a person is a carrier for a specific disorder. If the partner is also a heterozygote, the couple is at risk of having an affected child. Screening allows the couple to make informed reproductive choices. |
杂合子筛查 由于某些易患人群中有较高的杂合子发生率, 在他们中筛查某些疾病是合适的（如在以色列的阿斯克那士犹太人中查Tay-Sachs病,黑人中查镰状细胞贫血,少数民族中查地中海贫血）.通过杂合子筛查可以确定一个人是否携带某种特殊疾病的基因.如其配偶也是杂合子,他们的孩子就很可能患病.筛查可使都是杂合子的夫妇作出相应的生殖选择. |
| Presymptomatic genetic screening:Presymptomatic genetic screening may be appropriate for persons with a family history of a dominantly inherited disorder （eg, Huntington's disease, breast cancer）. Identifying a definite carrier of the genetic disorder may allow the patient to make informed decisions （eg, monitoring in the case of breast cancer, reproductive choices in the case of Huntington's disease or adult polycystic kidney disease）. |
症状前遗传筛查
症状前遗传筛查适用于家族史中有显性遗传病的人（如遗传性舞蹈病,乳腺癌）.如确定某人带有遗传病基因,可使该病人作出相应的决定（如带有乳腺癌基因者应定期检查,带有遗传性舞蹈病或成人多囊肾基因者的生殖选择）. |
| Prenatal diagnosis: Amniocentesis, chorionic villus sampling, umbilical cord blood sampling, maternal blood sampling, maternal serum screening, and fetal visualization with ultrasound and radiography are useful in prenatal diagnosis. Common reasons for prenatal screening include maternal age > 35 yr, a family history of a condition that can be diagnosed by prenatal techniques, abnormal maternal serum screening results, and certain complications of pregnancy. |
产前诊断羊膜腔穿刺,绒毛膜绒毛采样,脐带血检查,母血检查,母血清筛查,胎儿超声检查和X光摄片等都可用于产前诊断.母亲年龄大于35岁,家族史中有某种情况可由产前检查技术诊断者,母血清筛查结果异常者,某些妊娠并发症等都可进行产前筛查.
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| Newborn screening:Screening for phenylketonuria, galactosemia, and hypothyroidism in the newborn allows prophylaxis （ie, special diet or replacement therapy） to be initiated early enough to prevent severe complications. |
新生儿筛查对于苯丙酮尿症,半乳糖血症和甲状腺功能减退等应尽早筛查以预防发生严重的并发症.
家族系谱的建立 |
| Construction of a Family Pedigree The family history is often key to determining genetic risk. It is most easily recorded in a family pedigree （family tree）, which uses conventional symbols. The pedigree provides a ready view of problems or illnesses within the family and facilitates analysis of inheritance patterns, including the range and degree of affliction and variation among persons and generations. Some familial disorders with identical phenotypes have several patterns of inheritance. For example, cleft palate can have an autosomal dominant, autosomal recessive, or X-linked recessive pattern of inheritance, or it may be multifactorial （ie, familial but with no precisely predictable inheritance pattern）. |
家族史家族史常是确定遗传危险的关键. 在用约定俗成符号建立的家族体谱（家族树）中可以很方便地记录下家族史.在系谱中可以一目了然地看出该家族中的问题和疾患,并便于分析遗传类型,包括在各人和各代间疾患和变异的范围和程度.某些表型一样的家族性疾病可以有几种遗传类型.例如腭裂可以是常染色体显性遗传,常染色体隐性遗传或X伴性隐性遗传, 也可以是多基因遗传（即虽属家族性,但无明确预知的遗传类型）. |
| Generations in the family pedigree are numbered with Roman numerals, with older generations at the top and the most recent at the bottom. Within each generation, persons are numbered from left to right with Arabic numerals. Siblings are usually listed by age, with the oldest on the left. Thus, each member of the pedigree can be identified by two numbers （eg, II, 4）. A spouse is also assigned an identifying number. |
在家族系谱中,各代以罗马数字标记,最老的一代在顶部,最年轻的在底部.在同一代中,各人以阿拉伯数字从左往右标记.同胞兄弟姐妹按年龄大小排列,最年长者在左边.因此,系谱中每一成员可用两个数字来确定（如Ⅱ,4）.配偶同样有一个标记数字. |
| Study of a trait or disease begins with the affected person （the proband, propositus [male], proposita [female], or index case）. When taking a family history, the physician usually draws the pedigree as the relatives are described. The inquiry begins with the siblings of the proband and proceeds to the parents; relatives of the parents, including brothers, sisters, nephews, and nieces; grandparents; and so on. The number of relatives included in the pedigree is determined by the inheritance pattern of the condition and by the extent of the informant's memory or knowledge. Usually, at least 3 generations are included. Illnesses, hospitalizations, causes of death, miscarriages, abortions, congenital anomalies, and any other unusual features are recorded. |
对某一特征或疾病的研究要从患者开始（叫先证者）.医生采集家族史时,要按其亲属关系画出系谱.调查要从先证者的兄弟姐妹开始,然后涉及父母及父母的亲属,包括兄弟姐妹,堂表兄弟姐妹,还有祖父母,外祖父母等.系谱中亲属的数字决定于遗传类型和信息提供者的记忆能力和熟悉程度.通常,系谱至少包括三代人.患病,住院,死亡原因,小产,堕胎,先天性异常和任何其他异常均应记录在案. |
| Genetic Counseling Genetic counseling involves obtaining a thorough family history and addressing the family's concerns and questions by gathering appropriate information from the literature and from genetic specialists; consultation with an expert concerning the specific condition is often important. The information provided should include the diagnosis and diagnostic methods, including identification of carriers; the natural history of the disorder and its complications; the recurrence risk for the patient and various family members; potential therapies; and reproductive options. Communicating genetic risks and options is an involved process that often requires follow-up visits and written communication. |
遗传咨询 提供遗传咨询应详尽了解其家族史, 并根据从文献中和遗传学专家处收集的相关信息回答其关注的问题.对于特殊问题,请教有关专家常常是很重要的.提供的咨询包括诊断和诊断方法,携带者的鉴定；疾病发展及其并发症；病人及其家庭成员的复发危险；可能的治疗办法和生殖选择.传递遗传风险和选择是一复杂的过程,常须随访和书面沟通.
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Many family support groups exist for specific genetic diseases. Most have regular meetings with chapters in numerous locales and publish useful information.
Genetic counseling centers exist at medical schools in the USA and Canada. Patients and families can be referred for diagnosis, counseling, management, and information. A working relationship between the genetics center and the family physician is essential for the family's best interest and for follow-up. |
有很多支援小组对有特殊遗传病的家庭提供帮助.他们大多定期举行会议,在很多地方有分支机构并出版刊物.
在美国和加拿大的医学院校中都有遗传咨询中心.病人和家属可就诊断,咨询,管理和信息等问题前往求教.在遗传学中心和病人的家庭医师之间建立工作关系既符合病人家庭的最大利益也对随访有关键作用. |
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