医学遗传学课件：Clinical Cytogenetics

ClinicalCytogenetics:

DisordersoftheAutosomes

andtheSexChromosomesChromosomeDiseaseinClinicClinicalfeatureThegeneralfeaturesinautosomeabnormalitiesaretriadof

growthretardation,mentalretardation,and

specificsomaticabnormalities.Changeof

sexchromosome

alsohavetheabnormalitiesandmalformationsofinternalorexternalgenitalorgans.Trisomy21SyndromeTrisomy18SyndromeTrisomy13SyndromeCriDuChatSyndromeMicrodeletionSyndromeAutosomalDisorders

Trisomy21Syndrome

Asyndromeresultsfromcompleteorpartialtrisomy21chromosome,knownasDownsyndrome特殊面容：鼻梁低、眼距宽、外眼角上斜、耳位低、张嘴吐舌ClinicalFeatures

TheCategoryTrisomy21

47,XX(orXY),+2195%RobertsonianTranslocation4%

46,XX(orXY),-14,+t(14;21)(p11;q11)46,XX(orXY),-21,+t(21;21)(p11;q11)MosaicDownSyndrome1%

46,XX(orXY)/47,XX(orXY),+2147,XY,+21

EtiologyofTrisomy21RobertsonianTranslocation

46,XX(orXY),-14,+t(14;21)(p11;q11)Or46,XX(orXY),-14,+t(14q21q)BalancedTranslocationCarrier

45,XX,-14,-21,+t(14;21)(p11;q11)or45,XX,-14,-21,+t(14q21q)

14q21qTranslocationcarrier(viable)50%Trisomy2150%Monosomy21

21q21qTranslocationGermcellGametesZygotes2121q21qLost(abortion)(viable)NondisjunctioninmitosisMosaicDownSyndromeThegenesonchromosome21

Mentalretardation:

DSCAM、ADNP、DSCR1、ETS2

MNBH/DYRK1、SOD1Congenitalheartdefects,CHD:

COL6A1/2、

KCNE-2Leukaemia:

AML1

RiskofTrisomy21MotherageDownsyndromeincidence20~251:180025~291:150030~341:80035~391:25040~441:10045~1:50Trisomy18Syndrome

Thecategory

Trisomy18.80%

47,XX(orXY),+18

Mosaictrisomy18syndrome.10%

46,XX(orXY)/47,XX(orXY),+18ClinicalFeatures18三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.ClinicalFeaturesClinicalFeaturesGrowthretardationMentalretardationCongenitalheartdisease（先心）Rocker-bottomfeet（摇椅型足）fixedflexiondeformityofthefingers（手指弯曲畸形）Trisomy18Syndrome

EtiologyofTrisomy18Syndrome

RiskofTrisomy18Syndrome1/7500inliveborninfants,postnatalsurvivalispoor.About95%oftrisomy18conceptusesareabortedspontaneously.About80%ofthepatientsarefemale.Themotherolder,theriskofatrisomy18infantgreater

Trisomy13Syndrome

ThecategoryTrisomy13.80%

47,XX(orXY),+13RobertsonianTranslocation.14%

46,XX(orXY),-14,+t(13q14q)46,XX(orXY),-13,+t(13q13q)Mosaictrisomy13syndrome.6%

46,XX(orXY)/47,XX(orXY),+13ClinicalFeatures颅面的畸形包括小头，前额、前脑发育缺陷，2／3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，女性则有阴蒂肥大，双阴道，双角子宫等。智力发育障碍见于所有的患者，而且程度严重，存活较久的患儿还有癫痫样发作，肌张功力低下等.VaryingdegreesofmentalretardationCleftlip&Cleftpalate（唇裂腭裂）Polydactyly(postaxial)（多指）Equinovarus（马蹄内翻足）耳位低，耳廓畸形，眼球小，常有虹膜缺损，鼻宽而扁平，Trisomy13Syndrome

EtiologyofTrisomy13SyndromeusuallyarisesfromnondisjunctioninmaternalmeiosisI14%ofthecasesarecausedbyanunbalancedtranslocation

RiskofTrisomy13syndrome

1/22,700inliveborninfantsAbout50%oftrisomy13diewithinthefirstmonth.Asubsequentlivebornchildofonebalancedtranslocationcarrierwillhavethesyndromeislessthan2%.

CriDuChatSyndrome

Thekaryotype

46,XX(orXY),del(5)(p15)1in50000newbornsRound,moon-shapedface（满月脸）“Cryofthecat”（猫样哭声）VaryingdegreesofmentalretardationLowsetearsClinicalfeature:ClinicalFeaturesRiskofCriDuChatSyndrome1/50,000inliveborninfants.Thesyndromeaccountsforabout1%ofallinstitutionalizedmentallyretardedpatients.

EtiologyofCriDuChatSyndromeGenomicDisorders（基因组疾病）

某些综合征涉及以序列为基础的邻接基因重排机制，因而称为基因组病。

Severaldysmorphicsyndromeareassociatedwithsmall,butsometimescytogeneticallyvisible,deletions,leadingtoaformofgeneticimbalancereferredtoassegmentalaneusomy(部分异倍体).Thatcanresultincontiguousgenesyndrome.MicrodeletionandDuplicationSyndrome（微缺失和重复综合征）

MicrodeletionSyndrome22q11.22微小缺失：DiGeorge综合征腭帆-心-面综合征(velocardiofacial)面部畸形及心室流出道缺陷综合征

(conotruncalanomalyfacesyndrome)MicrodeletionorContiguousgeneSyndrome

RearrangementDisorderLocationTypeSize(kb)RepeatLength(kb)Smith-Magenissyndrome17p11.2Deletion5000200dup(17)(p11.2)DuplicationPrader-Willi/Angelmansyndromes15q11-q13Deletion4000~50—400DiGeorgesyndrome/22q11DeletionVelocardiofacial3000200syndromeCat-eyesyndromeDuplicationUnequalCrossingOverGeneAGeneBGeneCGeneAGeneBGeneCGeneAGeneBGeneCGeneAGeneBGeneCUnequalcrossingoverdeletionduplicationRepeatedsequences时间考场考生备注考试时间4月18日(周五)13：30-15：30待定预防-12（七年制)(80人)口腔11-1

(7人)答疑时间:4月9日(周三)

上午8:00-10:004月10日(周四)上午10:00-12:00待定口腔12-2(62人)医检-12(26人)待定医实-12(45人)临床11-8（25人）临床11-9（12人）待定临床11-7（25人）医英-11（35人）考试通知TheSexChromosomes

andTheirAbnormalitiesTheChromosomalBasisofSexDetermination

KaryotypePhenotype47,XXYmale(Klinefeltersyndrome)46,XXnormalfemale45,Xfemale(Turnersyndrome)46,XYnormalmale

TheYchromosomemakesacrucialroleinnormalmaledevelopment.TheYChromosomeSRY:sex-determiningregionofYchromosomeTDF：testis-determiningfactorSex-reversalDisorders

XXmales(46，XX)1/20,000birthsXYfemales(46,XY)1/20,000births

EtiologyofSex-reversalDisordersXTheXChromatin(theBarrbody)46,XX46,XY47,XXXTheLyonhypothesisInthesomaticcellsoffemalemammals,onlyoneXchromosomeistranscriptionallyactive.ThesecondXisheterochromaticandinactiveandappearsininterphasecellsassexchromatin,theBarrbody.Inactivationoccursearlyinembryoniclife.Inanyonefemalesomaticcell,theinactiveXmaybeeitherthepaternalorthematernalX,namelytheinactivationisrandomly.MaryF.Lyon

（1961）RandomX-chromosomeInactivationoccursearlyinembryoniclifeTheXInactivationCenter(XIC)

andtheXISTGene

TheXinactivationcenterhasbeenmappedtoproximalXq,inthebandXq13.TheXISTgeneisexpressedonlyfromthealleleontheinactiveX;ItistranscriptionallysilentontheactiveXinbothmaleandfemalecells.

XIST

:inactiveX(Xi)-specifictranscriptTheXInactivationCenter(XIC)andtheXISTGeneXq1345，X46，XX47，XXXKaryotypesandPhenotypesEscapeFromInactivationNonrandomXInactivationIncidenceofSexChromosomeAbnormalitiesSexDisorderKaryotypeApproximateIncidenceMaleKlinefeltersyndrome

47,XXY1/1000males48,XXXY1/25,000malesOthers(48,XXYY;1/10,000males49,XXXYY,mosaics)47,XYYsyndrome47,XYY1/1000malesXXmales46,XX1/20,000malesFemalesTrisomyX47,XXX1/1000females

Turnersyndrome

45,X1/5000females46,X,Xi(Xq)1/50,000femalesOthers(deletions,mosaics)1/15,000femalesXYfemales46,XY1/20,000females

Karyotype

47,XXY1/1000malelivebirths80%48,XXXY1/25,000males48,XXYY49,XXXYY1/1000malesmosaics15%

46,XY/47,XXY或46,XY/48,XXXY

KlinefelterSyndromeClinicalFeatures

身材较高，四肢细长，生殖器官发育不全，睾丸不发育或隐睾，曲细精管萎缩，呈玻璃样变性，无精子生成，不育，第二性征发育不良，女性化性状，有男子女性型乳房，因雌激素增高。KaryotypefromamalewithKlinefeltersyndrome(47,XXY)

EtiologyofKlinefelterSyndromePaternalmeiosisI1/2MaternalmeiosisI1/3MaternalmeiosisII/postzygoticmitosisremainderNondisjunctionoftheXandtheY1in1000malesTallstaturePredispositiontoviolent,＞180cm:1/200＞190cm:1/30＞200cm:1/10XYYsyndrome(47,XYY)CharacteristicsKaryotype45,X1/5000femalelivebirths50%

46,X,i(Xq)1/50,000females15%anddeletions…

Mosaics1/15,000females45,X/46,XX15%TurnerSyndromeClinicalFeaturesTurnerSyndrome(45,X)1in5000livebornfemalesCharacteristics

：Shortstature&Webbedneck（身材矮，有蹼颈）Ovariandysgenesis,primaryamenorrhea,infertility（卵巢发育不良，原发性闭经，不孕）Absenceofsecondarysexcharacteristics（第二性征不发育）Underdevelopedbreasts;widenipples（乳房发育不良，乳距宽）ClinicalFeaturesClinicalFeaturesClinicalFeaturesspontaneousabortions99%KaryotypefromafemalewithTurnersyndrome(45,X)FragileXSyndromeFragiles