文本讲义案例教案chromosome12a

ChapterFive

ChromosomeDisordersJinFan,jinfan@通知医学遗传学周测：时间：10月18早上8点至19日24点内容：“geneticsinmedicineandgenestructure”、“monogenicdisorders”和“chromosomaldisorders”。每单元约20题，90分钟答题时间。以后每周日0点至24点开放周测。网址：请用IE游览器上网，用户名和初始密码均为学号。如有问题邮件咨询助教：lricy1991@1.ChromatinandchromosomeEuchromatin:Slightlyandevenlystained,non-orlow-repetitiveDNAregionsHeterochromatin:Darklyandunevenlystained,highlyrepetitiveDNAregionsChromatininnucleusChromatincompositionDoublehelixNucleosomefiberSolenoidInterphasenucleusChromatinisthebasiccomponentsinthecellnucleusComposedofDNA,histonesandnon-histoneproteinsFromChromatintoChromosomeDifferentmodeofchromatininmetaphaseResultedfromhighlycompactionofchromatin:CellCycle

ChromosomePreparationCellculture:Peripheralblood:PHAstimulatingFibroblastfromvarouscellsBonemarrowforleukemiaAmnioticfluidcellforfetaldiagnosisColchicinearrestingmetaphase–HarvestagreatnumberofmetaphasesHypotonictreatmentChromosomespreadpreparationIdentifyeachchromosomescaffoldTelomereLongArmShortArmChromatidChromatids,twoafterS-phaseCentromereLongarmandshortarmTelomere2.Chromosomeidentification1.MorphologyofchromosomeLengthRL:Relativelength,ChL/totalLofahaploidsetPositionofcentromereAI:Armindex,LongarmL(q)/ShortarmL(p)CI:Centromereindex,q/ChLMetacentricCh.CI:1/2～5/8SubmetacentricCh.CI:5/8～7/8AcrocentricCh.CI:>7/8SatelliteCentromereMetacentricChSubmetacentricChAcrocentricChShortArmLongArmSatellitearmInternationalSystemforHumanCytogeneticNomenclature

ISCN,Denver1.Rl:fromlargetosmallChromosomelength:fromlongtoshort2.CI:fromsmalltolargeCentromereposition:fromlowtohigh3.Variableheterochromaticregion:1qh,9qh,16qh,YqSatelliteandsatellitearmofacrocentricchromosomesSexCh.46,XYKaryotyping,7GroupsABgroupCgroupDEgroupFGMMSubmMSubmSubmacrocacrocM2.BandingofchromosomeQbands:Caspersson(1970)QuinacrinemustardFluorescencemicroscopyBrightanddimbandsGiemsabands:TrypsindigestionGiemsastainingPermanentDarkandlightbandsGBandsReversedbands:Heated,KOHGiemsastainingPermanentDarkandlightbandsreversedtoGbandsRBandingHeated,KOHGiemsastainingHeterochromatininthecentromeres,longarmoftheYand1qh,9qhand16qhCBandsNomenclatureofhumanchromosomeSisterchromatidsShortArm,pLongArm,qTelomereZoneBandCentromereheterochromatinZonesandbandsofthechromosmebandzonearmChChromosomesindifferentstagesofphasesofcellcycleMoredetailedanalysisHigh-resolutionbandsFluorescenceInSituHybridization

（FISH）UsingDNAprobelabeledwithacertainmarkerHybridizingwithDNAinchromosomesandnucleionslidesProbeshybridizedwiththefragmentinchromosomearedetectedbysignalsfromthelabeledmarkersCh.+ProbeCo-(denature)(anneal)RapidmappingofgenesandsequencesinchromosomeDetectingsmallfragmentininterphase.Detectingcrypticrearrangementsorsmalldeletions–Bandingcouldnotbedetected<4MbFragileSites46,Y,fra(X)(q27-28)Non-staininggapsthatoccasionallyobserveratcharcteristicsitesonseveralchromosomesDependongrowthconditionsHeritablevariantsLabletestDNAwithgreenHybrizedontomalechromosomalpreparation1：1mixedLablenormalDNAwithredComparativeGenomicHybridization(CGH)CGHComparetheintensityoftwofluorochromesalongthechromosomeset.Detectionofduplicationordeletionofchromosomalsegment.ArrayCGH，aCGHEuploid46,XX46,XYarr(12)(pter-qter)×1,-12arr(9)(q12-qter)×3,(15)(q12-qter)×1,dert(12q;15q)3.Chromosomeabnormalities(1).NumericalchromosomalabnormalitiesHeteroploidy:Achromosomecomplementwithchromosomenumberotherthan46Euploidy:AchromosomecomplementwithanexactmultipleofthehaploidchromosomenumberAneuploidy:Achromosomecomplementwithchro-mosomenumberotherthananmultipleofthehaploidchromosomenumberA.Euploidy:

MonoploidyandPolyploidy1N:Monoploidy23Xor23Y:inparthenogenesis3N:Triploidy69,XXXor69,XXYinpartialmole,abortedfetusandlivebornwhodoesnotsurvivelong4N:Tetraploid92,XXXXor92,XXYYinabortedfetusTriploidy13-green,21-redTriploidyPat.diploidyover-growthoftrophoblastCompletemoleMat.diploidyover-growthofinnermasscellTeratomasTriploidyTwospermfertilizedwithanormaloocytePartialmoleparthenogenesisImprinting:Theexpressionofthephenotypedependsonwhetherthegeneorgenomeinheritedfromthefatherormother.Lossorgainofchromosomes(notmultipleofahaploidy)Monosomy2n-1:oneinsteadofapairofhomologouschromosomesTrisomy2n+1:threeinsteadofapairofhomologouschromosomes(2).AneuploidyMonosomyResultedfromnondisjunctionofthehomologouschromosomes(meiosisI)orsisterchromatids(mitosisormeiosisII).Trisomya.MonosomyAlmostallmonosomyforanentirechromosomeislethalTurner’ssyndrome:45,X,theonlymonosomycanbebornandsurvive45,XTypicalTurner’ssyndromeShortstatureGonadaldysgenesis:steakgonadsUnusualfaces,webbedneck,lowposteriorhairline,broadchestwithwidelyspacednipplesb.TrisomyTrisomy21,Down’ssyndrome47,XY,+21Trisomy21

Down’ssyndromeMostcommontrisomy1:800innewbornMostcommonsevermentalretardationEyeswithbrushfieldspotFlatnosalbridgeLowsetearOpenmouthwithprotrudingtongueShortandbroadhandwithasingletransversepalmarcreaseTrisomy21

Down’ssyndrome20-291;150030-341:100035-401:10040-451:40AgeofWomenBirthRateRelatedwithadvancedmaternalageTrisomy21

Down’ssyndromeTrisomy18

Edward’ssyndrome1:7500inlivebornandmorecommoninabortionandstillbirthSevermentalretardationandmultiplestructuralanomalies18-green,X-aquaTrisomy18

Edward’ssyndrome47,XY,+18Trisomy13

Patau’ssyndrome1:20,000inlivebornandmorecommoninabortionandstillbirthSeverstructuralanomaliesleadtodeathinonemonthTrisomy13

Patau’ssyndrome13-green,21-orange47,XY,+13XXY,Klinefelter’ssyndrome1:1,000inmalelivebornHypogonadismandInfertility:TallstatureLonglimbsSmallgenitaliaGynecomastiaXXY,Klinefelter’ssyndromeX-green,Y-red47,XXY47,XYYsyndrome1:1,000inmalelivebirthNormalintelligenceandnormalappearancebut:Educationalproblem:languagedelaysandspellingdifficultiesBehavioralproblems:attentiondeficits,hyperactivityandimpulsivenessFertilityproblem:increaseriskofchromosomalabnormalchild47,XYYsyndrome47,XYY47,XXXsyndrome1:1,000inFemalelivebirthNormalintelligenceandnormalappearanceAsignificantdeficitinperformanceonIQtests70%withsomelearningproblemsInfertility:50%47,XXXsyndrome47,XXXXXXXXSyndromeWhy?Autosome:onlytrisomy21,18and13foundinlive-birth,nomonsomySexchromosomeinlivebirth:XO,XXX,XXY,XYY,XXXX,XXXXX50,XXXXXXchromosomeinactivation

andXISTGenedosagecompensationisachievedinallpersonswithtwoormoreXchromosomesintheirgeneticconstitutionbypartialinactivationofallXchromosomesexceptone.TheprocessiscontrolledbyXIST(Xinactivespecifictranscripts)geneinXq13.2,whichencodesalargeRNAthatappearsto"coat"theXchromosomeandfacilitateinactivationofgenesontheXchromosome.Duringthelateblastocyststage,allXchromosomesexceptoneundergoheterochromatinizationandformXchromatinbodiesineachcell.ThebalanceofgenedosageonXchromosomeisachieved.TheexplanationofvariouskindsofXpolysomiesinlive-birth.Barrbody(3)MosaicandchimeraMosaicChimeraAberrationAberrationMosaicandchimera45,X/47,XXXResultedfromchromosomebreakageandreunion.BalancedstructuralabnormalityWithnormalcomplementofchromosomalmaterialUnbalancedstructuralabnormalityWithlossorgainofchromosomalmaterial(2).Abnormalitiesof

chromosomestructurea.Unbalanced

structureabnormalityDeletion:LossofachromosomesegmentResultedfrombreakageorunequalcross-overorsegregationofbalancedabnormalityCriDuChat(5p-)syndromeDeletion:5p15CryingsoundslikeanewingcatTypicalfeatures:hypertelorism,epicanthusandretrognathiaCriDuChat(5p-)syndrome5-p-telomere-green46,XY,5p-;46,XY,del(5p15:)46,XY,del(5)(p15:)46,XY,del(5)(qter-cen-p15:)4p-syndrome46,XX,del(4)(p16:)Deletionof22q-,Mosaic46,XY(40)/46,XY,del(22)(q13:)(10)

DuplicationGainofaextractchromosomesegmentinthesamechromosomeResultedfromunequalcross-overorsegregationofbalancedabnormality18q2318Dup(18)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)InsertionGainofaextractchromosomesegmentfromthedifferentchromosomeResultedfromsegregationofbalancedabnormalityFather46,XY,t(3;11)(q27;q13),ins(11;3)(q13;p26p13)Son46,XY,der(11)ins(11;3)(q13;p26p13)IsochromosomesOnearmisdeletedandtheotherduplicatedOnearmismonosomyandotheristrisomyThemostcommonisochromosomeisi(Xq)46,X,i(Xq)RingchromosomesFormedwhenachromosomeundergoestwobreaksandbrokenendsofthechromosomereuniteinaringstructure46,X,r(X)Ringchromosome,unstableSummary

ofchromosomenumberabnormalityDeletionDuplicationInsertionRingchromosomeIsochromosomeWithnormalcomplementofchromosomalmaterialUsuallyhavenophenotypiceffectsRepeatedabortion,intrauterinefetaldeath,stillbirthandbirthdefectsduetotheabnormalsegregationofinvolvedchromosomesinmeiosisb.Balancedstructureabnormality

(a)InversionsAsinglechromosomeundergoestwobreaksandisreconstitutedwiththesegmentbetweenthebreaksinverted.InversionofChromosome146,XX,inv(1)46,XY,inv(1)46,XX,inv(1)(q24q32)Pericentric:involvingcentromereParacentric:notinvolvingcentromereUsuallynoabnormalphenotypeAinversionloopisformedbetweenthepairofchromosomesandmayleadtoproduceunbalancedgametesoroffspring:InversionsPericentricinversionTheproductsofmeiosis1/4：Normal1/4：Inversion1/2：PartialtrisomyandpartialmonosomyAinversionloopParacentricinversionTheproductsofmeiosis1/4：Normal1/4：Bicentricch.1/4：Acentrisfrag.1/4：InversionAinversionloopReciprocal~Resultedfrombreakageofnonhomologouschromosomes,withreciprocalexchangeofthebroke-offsegmentsTranslocationReciprocalTranslocation(9;22)t(9;22)(q34;q12)t(9;22)(9pter-cen-9q34::22q21-22qter;22pter-cen-22q21::9q34-9qter)Reciprocaltranslocationinmeiosis2:2separationHighRisktoproduceunbalancedoffspring2:2Abortion,Fetaldeath,Birthdefects1/18Normal,1/18carrier，8/9variouskindsofunbalancedPossibleoffspringsofReciprocaltranslocationAbortion,Fetaldeath,BirthdefectsMother:46,XX,t(11;22)(q24;q12)NormalphenotypeSon:

47,XX,+der(22)t(11;22)(q24;q12)matMentalretardationMultiplestructuralabnormalitiesUnbalancedderivatedfromreciprocaltranslocationoftheparents45,XY,-22,der(6)t(6;22)(p25.3;q11.2)45,XY,-22,der(6)t(6;22)(6qter-cen-6p25.3::22q11.2-22qter)RobertsonianTranslocationTwoacrocentricchromosomesfusenearthecentromereregionwithlossoftheshortarms,whichcarrymultiplecopiesofgenesforrRNA.Only45chromosomeswithbalancedkaryotypeandphenotype45,XX,robt(13q14q)t(14q21q)1421OffspringofRob.translocationNormal,Carrier,Tri14,Mono14,Tri21,Mono21FertilizedbynormalgameteGametesZygotesMeoisisLimitationofresolutionofmicroscopy:>4MbDNADuplicationordeletion<4MbDNA:MicrodeletionMicroduplicationDiagnosiswithFluorescentin-situhybridization(FISH)withspecificDNAprobeorcomparativegenomichybridization(CGH)(3)Chromosomalmicro-abnormalityParader-WilliSyndromes

(PWS)ExcessiveeatingandObesitySmallhands,feetandshortstatureHypogonadismMentalretardationAngelmanSyndromes

(AS)Unusualfacialappearance,ShortstatureSpasticity,SeizureSmentalretardation

PWSAS46,XXorXY,del(15)(q11-q13)70%paternal70%maternalSimilardeletion,Differentorigin,AssociatedwithgeneimprintingDiGeorge(velo-cardio-facial,22q11.2deletion)syndromeCongenitalheartdisease(particularlyconotruncalmalformations)Palatalabnormalities[especiallyvelopharyngealinsufficiency(VPI)]HypocalcemiaImmunedeficiencyLearningdifficulties46,XX,del(22q11.2)WilliamssyndromeCharacteristicdysmorphicfacies,frequentlyreferredtoaselfinfacies(100%)Supravalvularaorticstenosis(80%)Variablementalretardation(75%)Characteristiccognitive/behavioralprofile(90%)Williamssyndrome

Deletionof7q11.23orelastingene46,XY,del(7q11.23)

SteroidSulfataseDeficiencyandX-LinkedIchthyosisDeletionofXp22.3STS46,X,del(Xp22.3)X-linkedichthyosisshowingthick,large,polygonal,dark-brownscalesinvolvingtheextensor.Steroidsulfatasedeficiencyduringpregnancyincarrierfemales:LeadstoanoveralldecreaseinthelevelsofestrogenSteroidSulfataseDeficiencyandX-LinkedIchthyosisKallmann'ssyndrome

DeletionofXp22.3KALCongenitalreducedpituitarygonadotropicactivitywithresultingassociationofhypogonadism,eunuchoidismandanosmia.46,Y,del(Xp22.3)

Summaryof

Chromosomedisorders

DuplicationordeletionofthecertainchromosomesorthecertainchromosomalsegmentsNumberorstructureabnormality0.6%inlivebirthand50%inspontaneousabortionsinfirst-trimesterinmicroscopicobservationSummaryof

ChromosomedisordersInvolvingthechangesofagroupsofgenes:complicatedsymptomSyndrome:Featuredbyseriousmentalretardation,structuralabnormalityofface,bodyandmultipleorgansHermaphroditismSexDifferentiationGenes,ChromosomeOvaryandTesitisHormone:femalehormones,MalehormonesMallerianduct:uterus,fallopiantubeWolffianduct:epididymis.glandulaseminalisExteriorgenitaliaSocial,BrainSexDifferentiationTwointactandnormallyfunctioningXchromosomes,intheabsenceofaYchromosomeleadtotheformationofanovaryFemalesexdifferentiationwilloccurinthepresenceofanovaryorstreakgonadsorifnogonadispresent<8w:exteriorgenitaliainallfetusremainslikefemale'sFemalesexdifferentiationAYchromosomeorthepresenceofthetestis-determiningfactor(SRY)willleadtotesticularorganogenesisDifferentiationoftheexternalgenitaliaalongmalelinesdependsontheactionoftestosteroneandparticularlydihydrotestosteroneMalesexdifferentiationSRYFmm1.TrueHermaphroditismBothovarianandtesticulartissuearepresentinone(ovotestis)orbothgonads.Differentiationoftheinternalandexternalgenitaliaishighlyvariable,andmostoftentheyareambiguous.Atestisandovaryorovotestisislocatedinthethelabioscrotalfolds,inguinalcanalortheabdomenintheremainder.Auterusisusuallypresent,hypoplasticorunicornuate.Theovotestisisthemostcommongonadfoundintruehermaphrodites(60%),followedbytheovaryand,leastcommonly,1.1Phenotype:

Truehermaphrodites20%:46,XX/46,XY20%:46,XY:Y-to-XandY-to-autosometranslocations,hiddensexchromosomemosaicism,orchimerismcanexplainthepathogenesisinthesepatients.60%:46,XX1.2Karyotype:

TruehermaphroditesDiagnosisdependingonpathology!2.FemalePseudohermaphroditismAffectedindividualshavenormalovariesandmüllerianderivativesassociatedwithambiguousexternalgenitalia.Intheabsenceoftestes,afemalefetuswillbemasculinizedifsubjectedtoincreasedcirculatinglevelsofandrogensderivedfromafetalormaternalsource.Thedegreeofmasculinizationdependsuponthestageofdifferentiationatthetimeofexposure2.1

CongenitalAdrenalHyperplasiaMostcasesoffemalepseudohermaphroditismandaround50%ofallcasesofambiguousgenitaliaDefect