遗传2013clinical cytogenetics-2013

1、Clinical Cytogenetics:Disorders of the Autosomesand the Sex ChromosomesYuxia YangDepartment of Medical GeneticsPeking University Health Science CenterChromosome Disease in ClinicalClinical feature The general features in autosome abnormalities are triad of growth retardation, mental retardation, and

2、 specific somatic abnormalities. Change of sex chromosome also have the abnormalities and malformations of internal orexternal genital organs.Autosomal Disorders Trisomy 21 Syndrome Trisomy 18 Syndrome Trisomy 13 Syndrome Cri Du Chat Syndrome Microdeletion SyndromeTrisomy 21 Syndrome A syndrome resu

3、lts from complete or partial trisomy 21 chromosome,known as Down syndrome特殊面容：鼻梁低、眼距宽、外眼角上斜、耳位低、张嘴吐舌epicamthi alClinical FeaturesThe CategoryTrisomy 2147, XX(or XY), +21Robertsonian Translocation46, XX(or XY), -14, +t(14;21)(p11;q11)46, XX(or XY), -21, +t(21;21)(p11;q11)Mosaic Down Syndrome46, XX(or

4、 XY)/47, XX(or XY), +2195%4%1%47,XY, +21Etiology of Trisomy 21Robertsonian Translocation46,XX(or XY),-14,+t(14;21)(p11;q11) Or 46,XX(or XY),-14,+t(14q21q)Balanced Translocation Carrier45, XX,-14,-21,+t(14;21)(p11;q11)or 45,XX,-14,-21,+t(14q21q)14q21q Translocationcarrier(viable)21q21q TranslocationL

5、ostGerm cell2121q21qGametesZygotes50% Trisomy 21(viable)50% Monosomy 21(abortion)Mosaic Down SyndromeNondisjunction in mitosisThe genes on chromosome 21n Mental retardation:DSCAM、ADNP、DSCR1、ETS2MNBH/DYRK1、SOD1n Congenital heart defects, CHD:COL6A1/2、KCNE-2n Leukaemia: AML1Risk of Trisomy 21Mother ag

6、e 20 2525 2530 3435 3940 4445 Down syndrome incidence1 : 18001 : 15001 : 8001 : 2501 : 1001 : 50Trisomy 18 Syndrome The categoryu Trisomy 18.47, XX(or XY), +1880%uMosaic trisomy 18 syndrome.46, XX(or XY)/47, XX(or XY), +1810%Clinical Features18三体综合征的畸形主要包括中胚层及其衍化物的异常（如骨骼、泌尿生殖系统、心脏最明显）此外，接近中胚层的外胚层（如皮

7、肤皱褶、皮嵴及毛发等）及内胚层（如美克尔憩室、肺及肾）也异常。文献报道胚胎5周前发育正常，在妊娠第6-8周开始出现异常.Clinical FeaturesClinical Featureso Growth retardationo Mental retardationo Congenital heart disease（先心）o Rocker-bottom feet（摇椅型足）o fixed flexion deformity of the fingers（ 手指弯曲畸形）Trisomy 18 SyndromeEtiology of Trisomy 18SyndromeRisk of Tris

8、omy 18Syndromeu 1/7500 in liveborn infants, postnatal survival is poor.u About 95% of trisomy 18 conceptuses are aborted spontaneously.u About 80% of the patients are female.u The mother older, the risk of a trisomy 18 infant greaterTrisomy 13 Syndrome The categoryu Trisomy 13.47, XX(or XY), +13u Ro

9、bertsonian Translocation. 46, XX(or XY), -14, +t(13q14q) 46, XX(or XY), -13, +t(13q13q)u Mosaic trisomy 13 syndrome.46, XX(or XY)/47, XX(or XY), +1380%14%6%Clinical Features颅面的畸形包括小头，前额、前脑发育缺陷，23患儿有上唇裂，并常有腭裂，耳位低，耳廓畸形，颌小，其它常见多指（趾），手指相盖叠，足跟向后突出及足掌中凸，形成所谓摇椅底足。男性常有阴囊畸形和隐睾，女性则有肥大，双，双角子宫等。智力发育障碍见于所有的患者，而且

10、程度严重，存活较久的患儿还有癫痫样发作，肌张功力低下等.o Varying degrees of mental retardationo Cleft lip & Cleft palate（唇裂腭裂）o Polydactyly (postaxial)（多指）o Equinovarus（马蹄内翻足）眼球小，常有虹膜缺损，鼻宽而扁平，耳位低，耳廓畸形，Trisomy 13 SyndromeEtiology of Trisomy 13 Syndrome usually arises from nondisjunction in maternal meiosis I 14% of the cases a

11、re caused by an unbalanced translocationRisk of Trisomy 13syndromen 1/22,700 in liveborn infantsn About 50% of trisomy 13 die within the first month.A subsequent liveborn child of one balanced translocation carrier will have the syndrome is lessthan 2%.Cri Du Chat Syndrome The karyotype46, XX(or XY)

12、, del(5)(p15)1 in 50000 newbornsClinical feature:o Round, moon-shaped face（满月脸）o “Cry of the cat”（猫样哭声）o Varying degrees of mental retardationo Low set earsClinical FeaturesRisk of Cri Du Chat Syndrome1/50,000 in liveborn infants.The syndrome accounts for about 1% of allinstitutionalized mentally re

13、tarded patients.Etiology of Cri Du Chat SyndromeGenomic Disorders（基因组疾病）Microdeletion and Duplication Syndrome（微缺失和重复综合征）Several dysmorphic syndrome are associatedwith small, but sometimes cytogenetically visible, deletions, leading to a form of genetic imbalance referred to as segmental aneusomy (部

14、分异倍体).That can result incontiguous gene syndrome.Microdeletion SyndromeMicrodeletion or Contiguous gene SyndromeRearrangementDisorderLocationTypeSize(kb)Repeat Length(kb)Smith-Magenis syndromedup(17)(p11.2)17p11.2DeletionDuplication500020050400200DiGeorge syndrome/22q11Deletion Velocardiofacial3000s

15、yndromeCat-eye syndromeDuplicationPrader-Willi/Angelmansyndromes15q11-q13Deletion4000Unequal Crossing OverdeletionRepeated sequencesGene A Gene BGene CGene AGene B Gene CduplicationGene A Gene BGene CGene AGene B Gene CUnequalcrossing overThe Sex Chromosomesand Their AbnormalitiesThe Chromosomal Bas

16、is of Sex Determinationn KaryotypePhenotypeThe Y chromosome makes a crucial role innormalmale development.45, Xfemale(Turner syndrome)46, XYnormal male47, XXYmale(Klinefelter syndrome)46, XXnormal femaleThe Y ChromosomeSRY: sex-determining region of Y chromosomeTDF：testis-determining factorSex-rever

17、sal Disorders XX males (46，XX)1/20,000 births XY females (46,XY)1/20,000 birthsEtiology of Sex- reversal DisordersXThe X Chromatin( the Barr body)46,XX46,XY47,XXXThe Lyon hypothesis1.In the somatic cells of female mammals, only one X chromosome is transcriptionally active. The second X is heterochro

18、matic and inactive and appears in interphase cells as sex chromatin, the Barr body.Inactivation occurs early in embryonic life.In any one female somatic cell, the inactive X may be either the paternal or the maternal X, namely the inactivation is randomly.2.3.Mary F. Lyon（1961）Random X-chromosome In

19、activationoccurs early in embryonic lifeThe X Inactivation Center (XIC)and the XIST GeneThe X inactivation center has been mapped toproximal Xq, in the band Xq13.The XIST gene is expressed only from the allele onthe inactive X; It is transcriptionally silent on theactive X in both male and female ce

20、lls.XIST : inactive X(Xi)-specific transcriptThe X Inactivation Center (XIC)and the XIST GeneXq13Karyotypes and Phenotypes45，X46，XX47，XXXEscape From InactivationNonrandom X InactivationIncidence of Sex Chromosome AbnormalitiesSexDisorderKaryotypeApproximate IncidenceMaleKlinefelter syndrome47,XXY1/1

21、000 males48,XXXYOthers(48,XXYY; 49,XXXYY, mosaics) 47,XYY1/25,000 males1/10,000 males47,XYY syndrome1/1000 males 1/20,000 males 1/1000 females 1/5000 females 1/50,000 females1/15,000 femalesFemalesTrisomy X47,XXX46,X,Xi(Xq)Others(deletions, mosaics)XY females46,XY1/20,000 femalesTurner syndrome45,XX

22、X males46,XXKlinefelter Syndromen Karyotype47,XXY48,XXXY48,XXYY49,XXXYYmosaics46, XY/47, XXY1/1000male live births80%1/25,000 males1/1000males15%或 46, XY/48, XXXYClinical Features身材较高，四肢细长，官发育不全，不发育或隐睾，曲细精管征发育不良，女性化性状，有男子女性型激素增高。，因雌Karyotype from a male with Klinefelter syndrome (47, XXY)Etiology of

23、 Klinefelter SyndromePaternal meiosis IMaternal meiosis I1/21/3Nondisjunction of the X and the YMaternal meiosis II / postzygotic mitosisremainderXYY syndrome(47,XYY)1 in 1000 malesCharacteristicsoTall stature180 cm: 1/200190 cm: 1/30200 cm: 1/10oPredisposition to violent,Turner Syndrome Karyotype45

24、,X1/5000 female live births50%46,X,i(Xq)and deletions1/50,000 females15%Mosaics1/15,000 females45,X/46,XX15%Clinical FeaturesTurner Syndrome (45, X)1 in 5000 liveborn femalesCharacteristics ：o Short stature & Webbed neck（身材矮，有蹼颈）o Ovarian dysgenesis, primary amenorrhea, infertility（卵巢发育不良，原发性，不孕）o A

25、bsence of secondary sex characteristics（第二性征不发育）o Underdeveloped breasts; widenipples（发育不良，乳距宽）Clinical FeaturesClinical FeaturesClinical Featuresspontaneous abortions99%Karyotype from a female with Turner syndrome (45, X)Etiology of Turner SyndromeThe single X is maternal in origin in about 70% of casesFragile X SyndromeWhat is Fragile X Syndrome Fragile site Fragile XFragile X syndrome Karyotype46, fra (X) YIncidence1/4000 males1/4000 - 8000 femalesClinical