第九章单基因遗传病

Chapter9Single-genedisordersMonogenicdisorders单基因遗传病Single-genedisordersTransmissionpatternsofsingle-genedisordersSomeproblemsaboutsingle-genedisordersLocus（位点）-achromosomallocationAlleles（等位基因）-alternativeformsofthesamelocusMutation（突变）-achangeinthegeneticmaterial,usuallyrareandpathological（＜1%）Polymorphism（多态性）-achangeinthegeneticmaterial,usuallycommonandnotnecessarilypathological（＞5%）Genotype（基因型）-thegeneticconstitutionoftheorganismPhenotype（表现型）-theobservableexpressionofgenotypeDominanttrait（显性性状）-atraitthatshowsinaheterozygoteRecessivetrait（隐性性状）-atraitthatishiddeninaheterozygoteGlossary&DefinitionsHomozygote（纯合子）-aparticulargenewhenidenticalallelesofthegenearepresentonbothhomologouschromosomes.Heterozygote（杂合子）-agenelocuswhenitscellscontaintwodifferentallelesofagene.Hemizygote（半合子）-onecopyofageneisdeleted,orintheheterogameticsexwhenageneislocatedonasexchromosome.Glossary&DefinitionsOverviewDefinition:geneticdisorderscausedbyasinglemutantgenearecalledsingle-genedisorders.Collectionoffamilyhistory---Proband(先证者):probandisanaffectedindividualthroughwhomthefamilycametotheattentionoftheinvestigatoralsocalledindexcase.Overview---Takingafamilyhistory:①age,sex,parents,sibsandothernearrelatives.②miscarriageandstillbirth（流产和死产）?③consanguineousmarriage（近亲婚配）?④Parentsfromthesamegeographicareaorethnicisolate?⑤Diagnosisofthesimilarconditioninanyrelativeofthepatient.Overview---Takingafamilyhistory:⑥Exactrelationshipoftherelativestotheprobandandtooneanother.⑦Negativeinformationmaybeimportantasapositivefinding.---Pedigreechart(familytree):Pedigreechartisashorthanddiagram,whichshowataglancetherelationshipofaffectedrelativestothepropositus(先证者)andtooneanother.Symbolscommonlyusedinpedigreecharts爷爷无奶奶有大伯无爸爸有叔叔无二姑有小姑无女儿（我妻子）有大儿子无小儿子有大儿子有大姑有小儿子有女儿无儿子有先天性掌跖角化症（以掌跖表皮过度角化为主要特征的先天性遗传病）家系图。包括非综合征型掌跖角化症、综合征型掌跖角化症。例1家系分析IIIIII121234561234567例2：腓骨肌萎缩症（CMT）ABCCMTpedigreeinShandong,ChinaDE10p14D10S585DHTKD1D10S1705D10S570D10S506D10S1664D10S191D10S1653D10S1477Mb12.913.814.314.515.816.6aa151352485557919Exon123456789101112131415161754.25Kb485(p.Y485X)470GLMTQEEVSEIKSSYYAKLNDHLNNMAHYRPP501470GLMTQEEVSEIKSSYYAKLNDHLNNMAHYRPP501666GLMTPEEVSEIKASYYAKLNDHLTHIDHYNPP697471GLTTQEEVSEIKASYYVKLNGHLTHAAHYRPP502471GLMTQEEVSDIKTSYYTKLNDHLANVAHYSPP502470GLMTQEEVSDIKASYYAKLNGHLANVAHYSPP501476GLMTDEERSQIKTSYYATLNNQLTNMTLYSPP507470QVLSESKAKEMRDEYMKYLGEELALAPAYQPP501460GFTTEEAVKEQLQKHTEQLNNELKKVDSTVPI491HomosapiensPantroglodytesCanisfamiliarisBostaurusMusmusculusRattusnorvegicusDaniorerioDrosophilamelanogasterCaenorhabditiselegansc.1455T>GABCDEF485Y485XAnonsensemutationinDHTKD1causesCharcot-Marie-Toothdiseasetype2inalargeChinesepedigree.AmJHumGenet,2012,91(6)

OMIMStatisticsforOct.18,2014TypeAuto-somalX-linkedY-linkedMitochon-drialTotalGenedescription13963683483514729Geneandphenotype,combined8820292Phenotypedescription,molecularbasisknown39502874284269Phenotypedescriptionorlocus,molecularbasisunknown1543134501682Other,mainlyphenotypeswithsuspectedmendelianbasis1731113201846Total212751219596522618

MIM#615025

CHARCOT-MARIE-TOOTHDISEASE,AXONAL,TYPE2Q;CMT2QTEXT:Anumbersign(#)isusedwiththisentrybecauseofevidencethatCharcot-Marie-Toothdiseasetype2Q(CMT2Q)iscausedbyaheterozygousloss-of-functionmutationintheDHTKD1gene(614984)onchromosome10p14.Compoundheterozygousmutationinthisgeneresultsin2-aminoadipic2-oxoadipicaciduria(204750).

ForaphenotypicdescriptionandadiscussionofgeneticheterogeneityofaxonalCMT,seeCMT2A1.ClinicalFeatures:Xuetal.(2012)reporteda5-generationChinesefamilyfromtheShandongProvinceofChinaaffectedbyanautosomaldominantformofCMT2.Thisfamilywasascertainedthrougha40-year-oldmaleproband.Therewere8affectedindividuals,5malesand3females,among5generationswhohadsymmetricalmusclewastingandapredominatingweaknessofthedistalpartsofthelowerlimbs,decreasedorabsentdeeptendonreflex,andmildtomoderatedeepsensoryimpairment.Theinitialcomplaintsoftheprobandincludeddifficultywalkingandtrippingduetofootanddistallegweaknessattheageof15years.Neurologicexamatthattimerevealedmuscleatrophyinthedistalpartsoftheforearmsandinnerosseousmusclesofthehands.Thelowerlegsdevelopedseveremuscleatrophy,whichpresentedas'crane-leg-like'malformations.Motorneuronandsensoryneuronconductionvelocitieswerenormalintheupperlimbsbutreducedinthelowerlimbs.Musclebiopsyfromtheprobandshowedsmallangulatedmusclefibers,andelectronmicroscopyshowedsarcomeredisappearance,disorganizedmicrofilaments,andmitochondrialvacuolization.Amongtheotherindividualswhowereexamined,ranginginagefrom13to71years,allhadsymptomonsetbetweenages13to25years.Allexhibitedpescavusandhadsomedegreeofmotorandsensorydeficits,moresevereinlowerthaninupperextremities.Mapping:Xuetal.(2012)performedlinkageanalysisinaChinesefamilysegregatingaxonalCMTandfoundthatthephenotypewaslinkedtochromosome10p14-p13,spanninga5.41-MbregionbetweenD10S585andD10S1477.MolecularGenetics:Inall8affectedmembersofaChinesefamilysegregatingaxonalCMT,Xuetal.(2012)identifiedaheterozygousnonsensemutation(Y485X;614984.0004)intheDHTKD1gene.Themutationwasnotfoundinunaffectedindividualsinthefamilyorin250unrelatedcontrolindividuals.KnockdownofDHTKD1resultedindecreasedATP,totalNAD(+),andNADH,andNADHinvitro.REFERENCES:1.Xu,W.,Gu,M.,Sun,L.,Guo,W.,Zhu,H.,Ma,J.,Yuan,W.,Kuang,Y.,Ji,B.,Wu,X.,Chen,Y.,Zhang,H.,Sun,F.,Huang,W.,Huang,L.,Chen,S.,Wang,Z.AnonsensemutationinDHTKD1causesCharcot-Marie-Toothdiseasetype2inalargeChinesepedigree.Am.J.Hum.Genet.91:1088-1094,2012.TransmissionpatternsAutosomalDominantInheritance,AD(常染色体显性遗传)AutosomalRecessiveInheritance,AR(常染色体隐性遗传)X-linkedDominantInheritance,XD(X伴性显性遗传)X-linkedRecessiveInheritance,XR(X伴性隐性遗传)Y-linkedinheritance(Y伴性遗传)AutosomalInheritanceAD：DDAffected(Lethal)DdAffected(D:AffectedgeneddNormald:Normalgene)AR：DDNormal DdNormal(Carrier) ddAffected(D:Normalgened:Affectedgene)AD—HuntingtonDiseaseEarlymanifestations:Grimacing(扮鬼脸),twitching(颤搐),restlessUncontrollabledance-likemovements.Progressivedementia(痴呆)developingbetweentheageof30and45Rigidity(死板)andseizures(癫痫发作)commonwhenonsetinchildhoodGenemutation:4p16.3(CAG)nAD—Marfansyndrome--Dolichocephaly(长头)--Frequenthypotoniaandmuscularunderdevelopment--Long,thinextremities,kyphoscoliosis(脊柱后侧凸),andjointlaxity.--Decreasedratioofuppersegment(vertextopubis)tolowersegment(pubistosole).--Pectusexcavatum(漏斗胸).--Cardiovasculardiseasein60-80%ofcaseswithmitraldysfunctionbeingmostfrequentproblemGeneMutation:FBN1MarfansyndromeMultiplesynostosessyndromeisduetoamissensemutationinexon2ofFGF9gene.AmJHumGenet.2009,85:53-63.多发性骨性连接综合征MIM#612961

MULTIPLESYNOSTOSESSYNDROME3;SYNS3.Genemaplocus13q11-q12TEXTAnumbersign(#)isusedwiththisentrybecausethisformofmultiplesynostosessyndromeiscausedbymutationinthefibroblastgrowthfactor-9gene(FGF9;600921).Forageneralphenotypicdescriptionanddiscussionofgeneticheterogeneityinmultiplesynostosessyndromes,seeSYNS1(186500).CLINICALFEATURESWuetal.(2009)described12affectedindividualsfroma5-generationChinesefamilysegregatingautosomaldominantmultiplesynostosessyndrome,withfusionsofproximalinterphalangeal,carpal-tarsal,andhumeroradialjoints.Hearing,stature,andintelligencewerenormalinallaffectedindividuals.Onlymildsemidislocationorcubitalvalgusatelbowjointsorlimitationoffingerjointflexionwasfoundin4patientsaged11yearsorbelow,suggestingthatthephenotypeisagedependent.MAPPINGWuetal.(2009)performedlinkageanalysisina5-generationChinesefamilysegregatingautosomaldominantmultiplesynostosessyndrome,butfoundnolinkagetoknownlocionchromosomes17q22and20q11.2.Agenomewidescreenidentifiedasinglelocusonchromosome13q11-q12thatcosegregatedwiththedisease(maximum2-pointlodscoreof3.7atD12S1236).Finemappingandhaplotypeanalysisnarrowedthecriticalintervalto8.6MbbetweenD13S175andD13S221,aregioncontaining22candidategenes.MOLECULARGENETICSIna5-generationChinesefamilywithautosomaldominantmultiplesynostosessyndromemappingtochromosome13q11-q12,Wuetal.(2009)identifiedaheterozygousmissensemutationinthecandidateFGF9gene(600921.0001)thatsegregatedwithdiseaseandwasnotfoundin250unrelatedethnicallymatchedcontrols.REFERENCES1.Wu,X.;Gu,M.;Huang,L.;Liu,X.;Zhang,H.;Ding,X.;Xu,J.;Cui,B.;Wang,L.;Lu,S;Chen,X.;Zhang,H.;Huang,W.;Yuan,W.;Yang,J.;Gu,Q.;Fei,J.;Chen,Z.;Yuan,Z.;Wang,Z.:Multiplesynostosessyndromeisduetoamissensemutationinexon2ofFGF9gene.Am.J.Hum.Genet.85:53-63,2009.AD—matingtypeDdxddAffectedNormal(matingtype)OffspringGenotype：DdddPhenotype：AffectedNormalProbability：1/21/2Probabilityratio：1：1DddDddddDddd（2）DdxDdAffectedxAffected

OffspringGenotype：DDDdddPhenotype：lethalAffectedNormalProbability:1/42/41/4Probabilityratio:3：1AD—matingtypeDdDDDDddDdddAD----ModelpedigreeAD—geneticfeaturesTheoccurrenceandtransmissionofthetraitarenotinfluencedbysex.Malesandfemalesareequallylikelytobeaffectedandtotransmitit,includingfather-to-sontransmission.Thetraitappearstoeverygenerationwithoutskipping,manifestinglineardistribution（垂直分布）.Theaffectedsubjectsarecertaintohaveoneortwoparentsaffected.Theunaffectedparentsdonottransmitthetraitwiththeexceptionofanewmutation.Theprobabilityofhavinganaffectedchildforasinglebirthis0.5withoneaffectedparent(Ddxdd)and0.75withtwoaffectedparents(DdxDd).AR--example-1Albinism(白化症)Theskinispinkwhite,thehairsnowwhite,andtheiris(虹膜)colorred,or,inobliquelight(斜视),translucentgraytoblue.Theretinahasnovisiblepigment.Severephotophobia(羞明)andnystagmus(眼球振颤).AR--example-2Chondrodysplasia,Grebetype(软骨成长不全症II型(Grebe型)Feng,B.;Chen,RB.etal:AkindredofMiaonationalityaffectedwithGrebe-Quelce-Salgadoachondrogenesis.ActaGenet.Sin.12:378-386,1985Chondrodysplasia,GrebetypeAR—matingtypeMatingtypesandrecurrenceriskAaxAaGenotype：AAAaaaPhenotype：NormalCarrierAffectedProbability:1/42/41/4Probabilityratio:3：1AR—matingtypeMatingtypesandrecurrenceriskDDxDdDdxddQuasidominantinheritance(类显性遗传)AR—modelpedigreeTheoccurrenceandtransmissionofthetraitarenotinfluencedbysex.Malesandfemalesareequallylikelytobeaffectedandtotransmitit.Thetraitusuallyappearsamongsibs,manifestinghorizontaldistribution(水平分布).Theaffectedsubjectsusuallyhavephenotypicallynormalparentswhoarebothcarriers(DdxDd).Theprobabilityofhavinganaffectedchildforasinglebirthis1/4andthatofhavingacarrieramongnormalchildrenis2/3.ConsanguineousmarriagesuggestsARinheritance.AR—geneticfeaturesAscertainment:ThesearchforappropriatepedigreeinthehumanpopulationissaidtobeascertainmentCompleteascertainmente.g.AD:AaxaaIncompleteascertainmente.g.AR:DdxDdAscertainment&Correction(确认与校正)Weinberg(1912):Weingbergprobandmethod(先证者法)(directsibmethod)实际上是把同胞s转换为同胞组s-1。q=Affectedprogeny–No.ofprobandsTotalprogeny–No.ofprobandsCorrectionTESTFORRECESSIVEINHERITANCEOFPANCREASCYSTICFIBROSISWITHSINGLY-SELECTEDFAMILYDATACORRECTEDACCORDINGTOWEINBERGMETHODSibshipsizeObs.familiesTotalprogenyProgenycountNormalAffected(s)(F)(sF)=T(N)(R)122022510373264246241311Total15422022Aftercorrection,q(aa)=∑R’/∑T’=(∑R-∑F)/(∑T-∑F)=(22-15)/(42-15)=7/27=0.259Beforecorrection,itwouldbe22/42=0.5238witharelativelytoohighpresentationoftheaffectedchildreninthesample.X-linkedinheritanceXDAffectedXHXHNormalXRAffectedXHXhNormalNormalXhXhAffectedAffectedXHYNormalNormalXhYAffected**Hemizygote(半合子)XD—exampleVitaminD-resistantrickets(抗维生素D佝偻病)Hemizygote(半合子)males:VitaminD-resistantricketswithbowingofthelegsrecognizedininfancy.Heterozygotefemales:Onlyhypophosphatemiainsomeandfullmanifestationinothers.Genelocalization:Xp22XD—matingtypeMatingtypesandrecurrenceriskXX×XHYXD—matingtypeMatingtypesandrecurrencerisk:XY×XHXXDModelPedigreeThetraitappearsineverygenerationwithoutskipping,manifestinglineardistributionwithmoreaffectedfemalesthanaffectedmales.Theaffectedsubjectsarecertaintohaveoneorbothparentsaffected.Theunaffectedparentsdonottransmitthetraitwiththeexceptionofanewmutation.Affectedheterozygousfemalestransmittheconditiontohalftheirchildrenofeithersexandaffectedhomozygousfemalestransmittheconditiontoalltheirchildren,apatternindistinguishablefromADinheritance.Affectedhemizygousmaleshavealldaughteraffectedandallsonsnormal,withoutfather-to-sontransmission,apatterndistinguishablefromADinheritance.XD—geneticfeaturesXR—exampleDuchennemusculardystrophy(Duchenne型肌营养不良)Theaffectedboyhascalfmuscleoflowerlimbsappearingbeunusuallywell-developed,yetisweakandunabletowalkwell,pedalatricycle,orclimbstairs.Attemptingtorisefromasittingpositiononthefloor,hecharacteristically”climbsuphislegs”(Gowers’sign).Bythetimethepatientis10yearsold,heisusuallyconfinedtoawheelchair.Deathusuallyoccursbefore20yearsofageandiseitherduetorespiratoryinfectionorheartfailure.Gower’ssignXR—matingtypeMatingtypesandrecurrenceriskXX×XhYXR—matingtypeMatingtypesandrecurrenceriskXhX×XYXR—matingtypeMatingtypesandrecurrenceriskXhX×XhYXR—modelpedigreeTheaffectedpersonsaremostlymalesbornebycarrierfemaleswithextremelyrarefemalecases.Theaffectedmalesarerelatedtooneanotherthroughfemalecarrierrelatives,withmaternalgrandfatherandgrandsonbeingaffected(criss-crossinheritance,交叉遗传)andmaternaluncleandnephewbeingaffected(obliquedistribution，斜行分布).Whenanaffectedmalemarriedanormalfemale,alltheirchildrenarenormalwithdaughtersbeingtheobligatorycarriers.Ifhemarriedacarrierfemale,theprobabilityofbeingaffectedforaboyoragirlis1/2.Whenacarrierfemalewasmarriedtoanormalmale,theprobabilityofaboy’sbeingaffectedis1/2andthatofagirlbeingcarrierisalso1/2.XR--geneticfeaturesY--linkageinheritance

(全男遗传)Uptonow,thereareonly27kindsofY-linkedtraitsanddiseasesareidentified,thereareall-maleinheritanceThemale-specificregionofthehumanYchromosomeisamosaicofdiscretesequenceclasses,H.Skaletskyetal.

Nature423,825-837(19June2003)Someproblemsaboutsingle-genedisordersPenetrance&ExpressivityPhenocopyGenepleiotropy(genepleiotropism)GeneticheterogeneityGeneticanticipationOnsetatage/delayeddominanceSex-limitation&Sex-influenceParentalimprinting(geneticimprinting)GeneticconsequenceofX-inactivationPenetranceisthepercentagefrequencyofgeneticallysusceptibleindividuals(heteroyzgotesinAD/XDandhomozygotesinAR/XR)whoactuallyshowthetrait.Postaxialpolydactyly(AD)（轴后多指(趾)畸形）AffectedxNormal91familiesNormalxNormal24familiesTotal115familiesPenetrance=91/115x100%=79%Penetrance&Expressivity

外显率和表现度ADpedigree，II4non-dominantExpressivityreferstothedegreeofexpression.Itmayroughlyequatedwithclinicalseverity.Atraitmayvaryinexpressionfromseveretomild.Anextremelymildandclinicallyinsignificantexpressionofanabnormality,diseaseorsyndromeiscalledaFORMEFRESTE(顿挫型).Expressivity(表现度)Phenocopy(拟表型)Anenvironmentallycausedconditionwhichresemblesoneknowntobeinherited.e.g.kwashiokor(恶性营养不良症)≈AcquiredalbinismGenepleiotropy(genepleiotropism)基因多效性Althougheachnormalgenehasonlyoneprimaryeffect,asinglemutantgeneorgenepaircanproducemultiplephenotypiceffectsthroughdiversesecondarypathways.Forexample:Phenylketonuria(PKU)---Primarygeneticdefect:Phenylalaninehydroxylasedeficiencyresultinginhyperphenylalaninemia(AR)---Multiplesecondaryeffects:Severementalretardation;Hairandskinfairerthannormalduetoimpairedmelaninsynthesis;Mousyormustysmell;Hypermyotonia;Hyperkinesis(运动过度).Ifmutationsatdifferentlocicanindependentlyproducethesamephenotypeorverysimilarphenotypesthataredifficulttodistinguishclinically,thephenotypeissaidtobegeneticallyheterogeneous.Geneticheterogeneityandphenotypicheterogeneity先天性耳聋家系DDeeddEEDdEeGeneticanticipation

(遗传早现)Theapparenttendencyofcertaininheriteddiseasestoappearatearlieronsetagesandwithincreasingseverityinsuccessivegenerations.Itresultsfromdynamicmutationsoftrinucleotiderepeats.Alongwithexpansionofthesetrinucleotiderepeats,theonsetagewillgetearlierandtheclinicalfeaturessevererinsuccessivegenerations.UnstablemutationDiseaseRepeatsequenceNormalrange(repeats)Pathogenicrange(repeats)RepeatlocationHuntingtondisease(HD)CAG9-3536-100CodingKennedydisease(SBMA)CAG13-3040-62CodingSpinocerebellarataxia1(SCA1)CAG6-3839-80CodingSpinocerebellarataxia2(SCA2)CAG16-3036-52CodingMachado-Josephdisease(MJD,SCA3)CAG14-4060->85CodingSpinocerebellarataxia6(SCA6)CAG5-2021-28CodingSpinocerebellarataxia7(SCA7)CAG7-1937-220CodingSpinocerebellarataxia17(SCA17)CAG25-4247-55CodingDentatorubral-pallidoluysianatrophy(DRPLA)CAG7-2349->75CodingSpinocerebellarataxia8(SCA8)CTG16-37100->5003'UTRSpinocerebellarataxia12(SCA12)CAG9-4555-785'UTRMyotonicdystrophytype1(DM1)CTG5-3550-40003'UTRFragileXsiteA(FRAXA)CGG10-50200-20005'UTRFriedreichataxia(FA)GAA8-33100-900IntronicFragileXsiteE(FRAXE)CCG6-25>200PromoterOculopharyngealmusculardystrophyGCG68-13CodingExamplesofdiseasearisingfromtripletrepeatexpansionsPolyQdiseases多聚谷氨酰胺疾病（polyglutaminedisease），简称polyQ疾病，为一类遗传性神经退行性疾病，由基因编码区内CAG三核苷酸重复的异常扩展导致编码蛋白中多聚谷氨酰胺链延长，当达到一定的阈值时就引起的疾病。目前已发现9种PolyQ疾病，包括亨廷顿舞蹈病（HD）、齿状核红核苍白球路易氏体萎缩（DRPLA）、延脊肌萎缩症（SBMA）和6种脊髓小脑共济失调（SCA1、SCA2、SCA3、SCA6、SCA7和SCA17。PolyQ疾病的异常CAG重复序列呈现高度不稳定性，在代间遗传过程中具有不断扩展的趋势，导致子代发病年龄较父代提前，且病程进展快，即遗传早现现象。PolyQdiseasesPolyQ病大多于中青年期起病，进行性加重。尽管各种PolyQ病的致病基因编码蛋白功能各异，具有各自不同的选择性病理损害，但它们的致病基因具有极其相似的突变形式，且共同的病理特征为神经细胞的核内和胞浆内异常蛋白聚集。异常蛋白具有获得性毒性作用，相关的发病机制学说包括异常蛋白错误折叠和构象改变，翻译后加工（磷酸化等），分子伴侣相互作用，泛素-蛋白酶体系统（UPS）异常以及转录调节障碍等。Sex-limitation:Anautosomallytransmittedtraitisexpressedinonlyonesex.E.g.:Precociouspuberty(AD)男性性早熟Heterozygousboysdevelopsecondarysexualcharacteristicsandunderagrowthspurt