临床遗传学课件：绪论

1、Clinical Genetics临床遗传学,绪 论,一、临床遗传学定义和特点 遗传学和临床医学的交叉课程, 应用遗传学原理和方法开展人类遗传性疾病（inherited disease, genetic disorder）诊断、治疗和预防的科学。 医学遗传学（medical genetics）的分支, 1950s 末人类染色体病发现和医学遗传学建立以后逐渐发展起来 预修: 医学遗传学和诊断学,临床遗传学特点,1遗传病起因于遗传物质的突变 基因和染色体诊断（genetic diagnosis)是最重要的诊断手段,“”SRY 48 44 19 17 M,2遗传病具有家系成员反复发生的风险,家谱分析

2、 pedigree analysis 遗传咨询 genetic counseling 临床遗传学的重要内容,3遗传病多症重而无有效治疗方法,产前遗传学诊断（prenatal genetic diagnosis）预防遗传病患儿出生是临床遗传学最为有效的技术手段。,二、遗传学基本概念、原理复习,1.遗传的物质基础： DNA，基因组Genome, 基因 Gene Human genome: a haploidy set of chromosomes with the mitochondrial DNA, 3.1109 bp, enough for encoding: 1.5106 proteins

3、About 1% of genome directing the synthesizing proteins, coding for about 20,000 proteins Structural Gene Region Other: non-encoding regions,基因: A specific DNA segment containing the code for the amino acid sequence of a polypeptide chain controlling the expression of specific characteristics of a li

4、ving organism.,Gene: exon(外显子) and intron(内含子),heterogeneous nuclear RNA,Gene: regulatory regions,Flanking sequence: Regulatory regions on both sides, Promoter, Enhancer, Terminator Control the gene expression in correct location, time and amount,Gene Mutation Base substitution: Transition（转换） and t

5、ransversion（颠换）,Gene Mutation,From DNA， Chromatin to Chromosome,Chromosome is the carrier of genes. Genes are arranged linearly on the chromosomes.,Human Chromosome，46, XY，2N,经典遗传学：Mendelism,遗传的基本单位基因（gene）呈线状串联排列在染色体上 位二条同源染色体(homologous chromosome)相同位点的一对基因是等位基因（allele），控制同一性状，显性（dominant）或隐性（rece

6、ssive） 这对等位基因在减数分裂(meiosis)时会随同源染色体的分离（segregation）而分别进入不同的配子,排列在不同染色体上的非等位基因，通常控制不同的遗传性状，在减数分裂时自由组合(independent assortment)，进入不同的配子。 排列同一染色体上的非等位基因，虽然控制不同的遗传性状，但在减数分裂中一起运动、相互连锁（linkage）进入同一配子。连锁基因可通过同源染色体之间同源片段的互换而发生交换（crossover）。,Concepts,Allele（等位基因）: one of the variant forms of a gene at a parti

7、cular locus Wild Type（野生型）: normal allele, prevailing version Mutant Type（突变型）: a allele (DNA) that differ from the wild-type Polymorpholism（多态性）: 2 relatively common alleles,Genotype（基因型）: the set of alleles Phenotype（表现型）: the observable expression of a genotype Homozygote（纯合子）: an individual with

8、 identical alleles Heterozygote（杂合子）: an individual with different alleles Hemizygote（半合子）: an individual with an allele on X chromosome, but no corresponding locus on the Y chromosome.,Other concepts,遗传异质性, GeneticHeterogeneity,Penetrance（外显率）: the probability of a gene expression Expressivity（表现度）

9、: the severity of phenotype expression,三、遗传性疾病的概念和分类,Genetic disorder or inherited disease is the diseases caused by gene mutation or human chromosomal aberration. Classic or Mendelian genetic disorders 经典遗传性疾病 Somatic and mitochondrial genetic disorders体细胞和线粒体遗传疾病,Classic genetic disorders,1. Mutat

10、ion is transmitted from the germ cells of parents or occurred in the early stage of fertilized oocyte. 2. Mutation exists in the whole tissues of the body and remains for the whole life time of the individual. 3. Mutation will transmitted to the next generation. Chromosomal, monogenic, polygenic dis

11、orders,(1)染色体病,Duplication or deletion of the certain chromosomes or the certain chromosomal segments Numerical abnormality Structure abnormality 0.6 % in liveborn and 50% in spontaneous abortions in first-trimester in microscopic observation,1染色体数目异常 (Heteroploidy, 异倍体) A chromosome complement with

12、 chromosome number other than 46,Euploidy(整倍体异常): A chromosome complement with an exact multiple of the haploid chromosome number 1N: Monoploidy 23X or 23Y: in parthenogenesis (单性生殖),葡萄胎，畸胎瘤 3N: Triploidy 69, XXX or 69, XXY 部分性葡萄胎：流产、死胎、新生儿死亡 4N: Tetraploid 92, XXXX or 92, XXYY 流产,三倍体,parthenogenesi

13、s,基因印记: The expression of the phenotype depends on whether the gene or genome inherited from the father or mother.,失去或增加一条或数条 (not multiple of a haploidy) 染色体 单体：Monosomy 2n-1 三体：Trisomy 2n+1,非整倍体异常,1. 常染色体数目异常,所有常染色体单体都是致死的，无法在活产儿中发现 能够活产出生常染色体三体只有：21、 18、13 三体三种,Trisomy 21 Downs 综合征,Most common tr

14、isomy: 1:800 in new born 最常见的重度智力低下,47, XY, +21,出生率随女性年龄增高而增加,Trisomy 21 Downs 综合征,18三体 Edwards 综合征,1:7500 in liveborn and more common in abortion and stillbirth Sever mental retardation and multiple structural anomalies,47, XY, +18,13三体Pataus 综合征,1:20,000 in liveborn and more common in abortion and

15、 stillbirth Serious structural anomalies lead to death in one month,47, XY, +13,2. 性染色体数目异常,性染色体数目异常类型众多： 单体、三体、四体、多体 不仅可以活产出生，而且可以长期存活，临床表型改变远较常染色体数目异常轻,X单体,所有的染色体单体都是致死的 唯一的例外：Turners 综合怔: 45,X, 可一活产出生，长期存活,45,X,Typical Turners 综合征,Short stature Gonadal dysgenesis: steak gonads Unusual faces, webb

16、ed neck, low posterior hairline, broad chest with widely spaced nipples,XXY, Klinefelter 综合征,1:1,000 in male liveborn Hypogonadism and Infertility: Tall stature, Long limbs Small genitalia, Gynecomastia,47, XXY,47, XYY 综合征,47, XYY,1:1,000 in male live birth, Normal appearance but: Educational proble

17、m: language delays and spelling difficulties Behavioral problems: attention deficits, hyperactivity and impulsiveness Fertility problem: increase risk of chromosomal abnormal child,47, XXX 综合征,1:1,000 in Female live birth Normal intelligence and normal appearance A significant deficit in performance

18、 on IQ tests 70 % with some learning problems, Infertility: 50%,47, XXX,XXXXX 综合征,Why? 常染色体:只有21, 18 和 13三体可以活婴出生，无单体 性染色体活婴出生：XO, XXX, XXY, XYY, XXXX, XXXXX,49, XXXXX,X 染色体失活,Gene dosage compensation is achieved in all persons with two or more X chromosomes in their genetic constitution by partial

19、inactivation of all X chromosomes except one. The process is controlled by XIST (X inactive specific transcripts) gene in Xq13.2, which encodes a large RNA that appears to coat the X chromosome and facilitate inactivation of genes on the X chromosome.,受精卵发育到囊胚晚期, 每个细胞通常只有一条X仍保持正常活性状态，其他X染色体均将通过高度浓缩异

20、质化（ heterochromatinization） 失活 （inactivation) 一个个体X 染色体基因剂量因此获得平衡 各类X染色体数目和结构异常个体可以出生和长期存活，表型改变相对较轻的原因,X 染色体失活，Barr body,Resulted from chromosome breakage and reunion. Unbalanced structural abnormality 不平衡染色体结构异常 With loss or gain of chromosomal material Deletion, duplication, insertion, isochromoso

21、me and ring chromosome,2染色体结构异常 Structural Abnormalities,染色体不平衡结构异常,缺失: Loss of a segment,重复: Gain of a segment from the same chromosome,With loss or gain of chromosomal material,Cri Du Chat (5p-) syndrome,Deletion: 5p15 Crying sounds like a newing cat Typical features: hypertelorism, epicanthus and

22、 retrognathia宽眼距, 内此赘皮,缩颌,46, XX, del(5)(p15:),18q23,46,XY,dup (18)(q23),46, XY, dup(18)(pter -cen-q23:q23:qter),46,X, dup(X)(q13q26) 46, X, dup(X)(pter-q26:q13q26:q26-qter),Isochromosomes,One arm is deleted and the other duplicated,等臂染色体,46, X, i(Xq),46, X, r(X),Ring chromosomes,A chromosome losses

23、 ends of both arms and reunites in a ring structure,环状染色体,Limitation of resolution of microscopy: 4 Mb DNA Duplication or deletion 4 Mb DNA: Microdeletion Microduplication Diagnosis with Fluorescent in-situ hybridization (FISH) with specific DNA probe or comparative genomic hybridization (CGH),染色体微缺

24、失、微重复综合症,Parader-Willi 综合症(PWS),Excessive eating and Obesity Small hands, feet and short stature Hypogonadism Mental retardation,Angelman 综合症(AS),Unusual facial appearance, Short stature Spasticity,Seizure S mental retardation,Similar deletion, Different origin, Associated with gene imprinting,DiGeo

25、rge (velo-cardio-facial, 22q11.2 deletion) 综合症,Congenital heart disease (particularly conotruncal malformations) Palatal abnormalities especially velopharyngeal insufficiency (VPI) Hypocalcemia Immune deficiency Learning difficulties,46, XX, del( 22q11.2),Williams syndrome,Characteristic dysmorphic

26、facies, frequently referred to as elfin facies (100%) Supravalvular aortic stenosis (80%) Variable mental retardation (75%) Characteristic cognitive/behavioral profile (90%),46, XY, del(7q11.23),Mosaic and chimera,45,X/47,XXX,46, XY (40) / 46, XY, del(22)(q13:) (10),染色体病,Duplication or deletion of t

27、he certain chromosomes or the certain chromosomal segments： Numerical, unbalanced structural or micro-structural abn. Involving the changes of a groups of genes. Complicated symptom: serious mental retardation, structural abnormality of face, body and multiple organs Phenotypic alteration in sex chr

28、omosomal abnormalities is usually not so serious as in autosomal abnormalities. Phenotypic alteration in mosaic depends on the ratio of cell lines with chromosomal abnormalities,Balanced structural abnormality平衡染色体结构异常,Inversion (inv, 倒位）, reciprocal translocation (t, 相互易位 ), Robertsonian translocat

29、ion (rob,罗伯逊易位) Without loss or gain of chromosomal materials Usually phenotypic normal Repeated abortion, intrauterous fetal death, stillbirth and birth defects due to the abnormal segregation of involved chromosomes in meiosis,Pericentric inversion,The products of meiosis,Normal Carrier Partial de

30、letion and duplication,Paracentric inversion,The products of meiosis,Normal Carrier Acentric Bicentric,Reciprocal Translocation after meiosis and fertilization 1/18 normal, 1/18 carrier, 8/9 abnormal,总染色体物质无增加或减少 通常表型正常 但生育问题： 反复流产、宫内死胎、死产、出生缺陷 染色体异常携带者 染色体病患者以外的染色体异常,平衡染色体结构异常-染色体病携带者,Single gene d

31、efects Caused by an individual mutant gene and transfer through the generations according to Mendelian genetics Individual incidence rate is rare Total incidence is 1.00% in live births and 6-8% in hospitalized children,(2) 单基因病 Monogenic disorder,Balanced translocation in meiosis and offsprings,Hig

32、h Risk to produce unbalanced offspring,2:2 separation,1常染色体显性遗传病 Autosomal Dominant,The trait appears in every generation Any child of an affected person has a 50 percent risk of inheriting the trait. Unaffected family members do not transmit the trait to their children The occurrence and transmissi

33、on of the trait are not influenced by sex,Ocular (眼) Lens dislocation (晶状体脱位) Cardiovascular (心血管) Aortic anomalies (主动脉畸形) Mitral valve prolapse (二尖瓣脱垂) Musculoskeletal (肌肉骨骼) Change of height/span(指距)and US/LS Pectus deformities(胸畸形) Dural ectasia (硬脊膜膨出),Marfan Syndrome,Clinic Features Blue scler

34、a Bone fragility Short stature Dentinogenesis insufficiency Hearing loss Reduced life span,Osteogenesis Imperfecta (OI) （成骨发育不全）,Huntington Disease (HD),Onset: 35 to 44 ys (delayed onset) A progressive disorder of motion, cognitive, and psychiatric disturbances The median survival time: 15 to 18 yea

35、rs after onset,dilatation of ventricles, atrophy of caudate nucleus,2 常染色体隐性遗传病 Autosomal Recessive,The trait characteristically appears only in sibs, not in their parents. On the average, one fourth of the sibs of the proband are affected The parents of affected child may be consanguineous. Males and females are equally likely to be affected.,Albinism白化病,A group of recessive genetic disorders of melanin synthesis resulting in congenital hypopigmentation(色素沉着不足). Mutations in at least 12 genes Locus heterogeneity,Sickle cell anemia,A defect (Glu6Val缬) in 146 aa beta-hemoglobin (H