医学遗传与胚胎发育：9 Single-gene disorders Monogenic disorders

Single-genedisorders

Monogenicdisorders

OverviewAsingle-genedisorderisadiseasecausedbymutationwithinasinglegene.Single-genedisordersareinheritedinsimplepatternssimilartothosedescribedbyMendelforcertaindiscretecharacteristicsingardenpeas.Single-genedisordersarealsonamedasMendeliandisorders.i.e.Theyoccurinfixedproportionsamongtheoffspringofspecifictypesofmating.Mendel'sLawsofInheritanceLawofSegregationLawofIndependentAssortmentLawofDominanceTerminologyGene

-Thebasichereditaryunit.Bymoleculardefinition,geneisaDNAsequencerequiredforproductionofafunctionalproduct,usuallyaprotein,butmaybeanuntranslatedRNA.Allele(等位基因）

-Analternateversionofagene,orofaDNAsequence,atagivenlocus.Locus（基因座/位点）

-Literallya“place”onachromosomeorDNAmolecule.Usedfairlytorefertoaspecificgeneandsometimesusedtorefertoacollectionofcloselyspacedgenes.Dominanttrait（显性性状）-

atraitthatshowsinaheterozygoteRecessivetrait（隐性性状）

-atraitthatishiddeninaheterozygote.i.e.thedisease(recessivetrait)occursonlywhenanindividualishomozygousforthemutantallele.Homozygote（纯合子）

-Theindividualwhohavetwoidenticalallelesataparticularlocus,usuallyinreferencetotwonormalallelesortwodiseasealleles.Heterozygote（杂合子）

-Theindividualwhohavetwodifferentallelesataparticularlocus,usuallyinreferencetoonenormalalleleandonediseaseallele.Compoundheterozygote（复合杂合子）-Theindividualwhohavetwodifferentmutantallelesofthesamegene,ratherthanonenormalandonemutant.Wild-type(normal)allele:prevailingversion,presentinmajorityofindividuals.Mutantallele:usuallyrare,differfromwild-typeallelebymutationMutation:permanentchangeinnucleotidesequenceorarrangementofDNAPolymorphism:≥2relativelycommon(each>1%inpopulation)allelesatalocusinthepopulationGenotype:Anindividual’sgeneticconstitution,eithercollectivelyatalllociormoretypicallyatasinglelocus.Phenotype:Observableexpressionofgenotypeasatraitordisease(morphological,clinical,biochemical,ormolecular).PrefixAutosomalXLinkedYLinkedMitochondrialTotals*

Genedescription14,115695483514,893+

Geneandphenotype,combined8420288#

Phenotypedescription,molecularbasisknown4,0842914284,407%

Phenotypedescriptionorlocus,molecularbasisunknown1,529130501,664

Other,mainlyphenotypeswithsuspectedmendelianbasis1,715113201,830

Totals21,5271,231596522,882NumberofEntriesinOMIM

(UpdatedApril24th,2015)

:AlthoughmostMendeliandiseasesarerare,affectingindividuallyabout1/10,000to1/100,000livebirthsasanorderofmagnitudeestimate,about3%-5%ofhumanpopulationareaffectedbysingle-genedisorders.Single-genedisordersareprimarilydisordersofthepediatricagerange;lessthan10%manifestafterpuberty,andonly1%occuraftertheendofthereproductiveperiod.MajortopicsPatternsofsingle-geneinheritanceFactorsaffectingpatternsofsingle-geneinheritancePatternsofsinglegenedisordersFactorsdeterminingtheclassificationChromosomelocationDominantorrecessive

Basicpatternsofsinglegenedisorders

DominantRecessiveAutosomalAutosomaldominant(AD)Autosomalrecessive(AR)X-linkedX-linkeddominant(XD)X-linkedrecessive(XR)Y-linkedY-linkedPedigreeanalysisPedigreeanalysisTheinheritancepatternsofmostMendeliantraitshavebeendeducedfromobservingthesegregationortransmissionofthesetraitswithinfamilies.ThisprocessisPedigreeanalysis.Apedigree(系谱)

isafamilytreewhichismadeupofsymbolsandlines.Pedigreerepresentsapatient'sgeneticfamilyhistory.

Proband

(propositusorindexcase,先证者):

istheaffectedindividualthroughwhomafamilywithageneticdisorderisfirstbroughttoattention.note:Probandisapatient.Pointstoremember:askwhetherrelativeshaveasimilarproblemaskifthereweresiblingswhohavediedinquireaboutmiscarriages,neonataldeathsbeawareofsiblingswithdifferentparentsaskaboutconsanguinityaskaboutethnicoriginoffamilybranches

Autosomaldominantinheritancegenotype

phenotypeAAAffected(lethal)AaAffectedaaNormal(A:diseasegenea:Normalgene)Majormatingtypesand

probabilityofoffspringofADAa×aaAa×AaQuestion:Couldyoutelltheprobabilityofeachoffspringoftheabovematingtypes?AtypicalpedigreeofADEachaffectedindividualhasoneaffectedparent.Unaffectedparentsdonottransmitthephenotypetotheirchildrenwiththeexceptionofnewmutation,nonpenetrantorsubtleexpression.Thephenotypeusuallyappearsineverygeneration,passedinaverticalfashion.Anychildofanaffectedparenthas50%riskofinheritingthetrait.Malesandfemalesareequallylikelytotransmitthephenotype,tochildrenofeithersex.Inparticular,maletomaletransmissioncanoccur,andmalescanhaveunaffecteddaughters.AD-PedigreeCharacteristicsExampleofAD--Huntington’schoreaAgeofonset:30-45Earlymanifestations:Grimacing(扮鬼脸),twitching(颤搐),restlessProgressiveuncontrollabledance-likemovementsProgressivementalretardation,dementia(痴呆)Rigidity(死板),seizures(癫痫发作)Genemutation:4p16.3(CAG)nThemutationisanabnormallylongexpansionofastretchofthenucleotide

CAG,thecodenofglutamin.Normalindividualscarry9-35CAGrepeats,onceanexpansionincreasestogreaterthan39,diseasealwaysoccurs,andthelargertheexpansion,theearliertheonsetofthediseaseandthesevererthemanifestations.

ExampleofAD–MarfansyndromeDolichocephaly(长头);Long,thinextremities;Decreasedratioofuppersegment(vertextopubis)tolowersegment(pubistosole).---overgrowthFrequenthypotonia(张力减退);kyphoscoliosis(脊柱后侧凸),andjointlaxity;pectusexcavatum(漏斗胸)Cardiovasculardiseasein60-80%ofcasesmostlyshownasmitral(二尖瓣)dysfunction;aorticaneurysmEyedisease:dislocatedlens,detachedretinaGeneMutation:FBN1脊柱侧凸正常脊柱漏斗胸鸡胸NormalBodyMarfanSyndromeFibrillinFibrillinisthemostimportantandmajorcomponentofmicrofiber,whichisthemajorcomponentofelasticfiber.Elasticfiberisthemajorcomponentofsupportingtissues.Microfiberisaimportantreserve(sequestered)bankoftransforminggrowthfactorβ(TGF-β),whichplaysimportantrolesinregulatingcellgrowth.ExampleofAD--multiplesynostosessyndrome3,(SYNS3),MIM612961

Brachydactylia(短指（趾）畸形)、ankylosisandfusionofjoints(关节强直或融合)Amissensemutation(S99N)inthe99thcodonoffibroblastgrowthfactor9(FGF9)leadstothisdisease.WuXL，GuMM，HuangL，etal.Multiplesynostosessyndromeisduetoamissensemutationinexon2ofFGF9gene[J].AmJHumGenet,2009(1):53-63.

Autosomalrecessiveinheritancegenotype

phenotypeAANormalAaasymptomaticcarrier(无症状携带者）aaAffected(A:Normalgenea:diseasegene)Majormatingtypesand

probabilityofoffspringofARAa×Aa*1Aa×aaAa×AAaa×aaQuestion?Fortheoffspringof

Aa×AamatingtypeinARdisease,amongthesiblingswithnormalphenotype,

whichisthecorrectproportionofasymptomaticcarriers?

A3/4B1/2C2/3D1/4AR-TypicalpedigreeAR-PedigreeCharacteristicsIfthedisorderappearsinmorethanonefamilymember,typicallyitisfoundonlywithinasibship,notinothergenerations,showingashorizonaldistribution.Normalparentsofanaffectedchildareasymptomaticcarriers(obligate

heterozygotes,必然杂合子).Therecurrenceriskforeachsiboftheprobandis25%.Morecommonwithconsanguinity,especiallyforrarediseases.Usually,malesandfemalesareequallylikelytobeaffected(withrareexceptions)Newmutationisalmostneveraconsideration.

ExampleofAR-Cysticfibrosis(CF)

Clinicalsymptomsincludepancreatic（胰腺）insufficiencyandpulmonaryinfectionsDiseasedhomozygotes:1/2000Carriers(heterozygotes):1/22Causedbymutationsinthecysticfibrosistransmembraneconductanceregulatorgene(CFTR)onchromosome7q31Multi-organ

SystemManifestationsofCFSecondarybiliarycirrhosis（继发性胆汁性肝硬化）Malabsorption（吸收障碍）Obstructedvasdeferens(sterility)（输精管阻塞）Meconiumileus（胎粪性肠梗阻）(newborn)Chronicpancreatitis（慢性胰腺炎）AbnormalsweatelectrolytesLungabscess（肺脓肿）Chronicbronchitis（慢性支气管炎）Bronchiectasis（支气管扩张）Honeycomblung（蜂窝肺）CFTRfunctionRegulatestheflowofchlorideionsacrossthecellmembraneHemizygote

HemizygotedescribesadiploidmalewhohasonlyonealleleontheX-chromosomeoroneX-chromosomeratherthantheusualtwoinadiploidfemale.MalecanonlyreceiveallelesontheX-chromosomefromhismotherandtransmitsittohisdaughter.Sonever

fathertosonormaletomaletransmission.Criss-crossinheritanceMajormatingtypesand

probabilityofoffspringofXDXHXh×XhYMajormatingtypesand

probabilityofoffspringofXDXhXh×XHYTypicalpedigreeofXD

Morefemalesaffectedthanmales,theratioisapproximately2to1Alldaughtersofaffectedmalesareaffected,allsonsofaffectedmalesarenormal,i.e.nomaletomaletransmissionAchildofanaffectedheterozygousfemalehas50%risktobeaffectedEachaffectedindividualhasoneaffectedparent,passedinaverticalfashionPedigreeCharacteristicsofXDExampleofXD

VitaminD-resistantricketsHemizygotemales:VitaminD-resistantricketswithbowingofthelegsrecognizedininfancy.Heterozygotefemales:Someonlyshowhypophosphatemiaandothersshowfullmanifestation.Genelocalization:Xp22PHEXgenecodesPHEXproteinwhichregulatesthetransportationofCalciumandPhosphorusbythekidney.

Theaffectedpersonsaremostlymalesbornebycarrierfemaleswithextremelyrarefemalecases.

Themutantalleleisordinarilynevertransmitteddirectlyfromfathertoson.Butitistransmittedbyanaffectedmaletoallhisdaughters,anyofhisdaughter’ssonshasa50%chancetobeaffected.---Criss-crossinheritance（交叉遗传）Themutantallelemaybetransmittedthroughaseriesofcarrierfemales;ifso,theaffectedmalesinakindredarerelatedthroughfemales.---obliquedistribution(斜行分布）PedigreeCharacteristicsofXR

exampleofXR

Duchennemusculardystrophy

unusuallywell-developed(pseudohypertrophy)calfmusclesweak,unabletowalkwell,pedalatricycle,orclimbstairsGowers’sign.Onsetinboysbeforeage5anddevelopprogressivelyDeathbefore20yearsoldeitherduetorespiratoryinfectionorheartfailureGenemutation:DMDgeneonXp21.1-Xp21.2Gowersign

ofDMDY-linkedInheritanceInheritanceofgenesontheYchromosome.SinceonlymaleshaveaYchromosome,Y-linkedgenescanonlybetransmittedfromfathertoson.HairyEars(MIM425500)HairyEars(MIM425500)e.g.FactorsaffectingpedigreepatternsAscertainment&CorrectionPenetrance&ExpressivityGenepleiotropy(genepleiotropism)AgeofonsetSex-limited&Sex-influencedinheritance21GeneticconsequenceofX-inactivationParentalimprinting(geneticimprinting)Consanguineousmating&CoefficientofkinshipGeneticheterogeneityGeneticanticipationPhenocopyAscertainment&Correction

(确认与校正)

Ascertainment:Thesearchforappropriatepedigreeinthehumanpopulation.Completeascertainmente.g.AD:Aa×aaIncompleteascertainmente.g.AR:Aa×AaInpractice,werecognizeobligateheterozygousparentsbythepresenceofanaffectedchild,iftheyhavenoaffectedchild,suchfamilieswouldnotbeascertainedintheabsenceofascreeningprogramfordetectingheterozygouscarriers.Penetrance（外显率）Penetranceisdefinedasthepercentageofindividualswithapredisposinggenotypewhoexhibitthephenotype,atleasttosomedegree.Penetranceisanall-or–noneconcept.Ifthephenotypeisalwaysexpressedwheneverthealleleispresent,thetraitisfullypenertrant;whileifthephenotypeisonlyexpressed

in

someindividualshavingthedisease-causinggenotype,thetraitisincompletelypenertant.Postaxialpolydactyly(AD)（轴后多指(趾)畸形）AffectedxNormal91familiesNormalxNormal24familiesTotal115familiesPenetrance=91/115x100%=79%Expressivity(表现度）Expressivityistheseverityofthephenotypeamongindividualswiththesamedisease-causinggenotype.Whentheseverityofdiseasediffersinpeoplewhohavethesamegenotype,thephenotypeissaidtohavevariableexpressivity.Theindividualswithoutclinicallysignificant

phenotypesarecalledformefruste（顿挫型）Genepleiotropy(genepleiotropism)

基因多效性

Althougheachgenehasonlyoneprimaryeffect,asinglemutantgeneorgenepaircanproducemultiplephenotypiceffectsthroughdiversesecondarypathways.Forexample:Phenylketonuria(PKU)---Primarygeneticdefect:Phenylalaninehydroxylasedeficiencyresultinginhyperphenylalaninemia(AR)---Multiplesecondaryeffects:Severementalretardation;Hairandskinfairerthannormalduetoimpairedmelaninsynthesis;Mousyormustysmell;Hypermyotonia;Hyperkinesis(运动过度).AgeofOnsetNotallgeneticdisordersarecongenital;somegenesarenotexpresseduntilatacharacteristicdevelopmentstageorageManygeneticdisordersdevelopprenatallyandthusarebothgeneticandcongenital(e.g.,osteogenesisimperfecta)Somemaybelethalinprenatallife.i.e.PersonsofsomegenotypesmayfailtosurvivetotimeofbirthOthersexpressedassoonastheinfantbeginsindependentlifeOthersappearlater,atavarietyofages(frombirthtopost-reproductiveyears)

Sex-limitedphenotype(限性遗传)Sex-limitedinheritance:Anautosomallytransmittedtraitisexpressedinonlyonesex.E.g.Precociouspuberty(AD)男性性早熟

Heterozygousboysdevelopsecondarysexualcharacteristicsandagrowthspurtatabout4yearsofageorevenyounger,becomingmuchtallerthantheirpeers.Becauseofearlyfusionoftheepiphyses(骨骺)ofthelongbonestheyendupasashortman.Sex-influenceddisorders(偏性遗传)

Sexinfluenceddisorders:Someautosomallytransmittedtraitsareexpressedmorefrequentlyormoreseverelyinonesexthananother.e.g.

Baldness(早秃)(ADinmales,ARinfemales)e.g.

Hemochromatosis(色素沉着病）excessivebodystoresofiron,morecommoninmales.X-inactivation

(X染色体失活)

Manifestingheterozygotes（显示杂合子）HeterozygousfemalesofX-linkedrecessivedisordersareusuallyunaffected,butsomemaymanifestsymptomswithvariableseveritydeterminedbythepatternofXinactivation.X–inactivation

is

random

andisatastageofembryonicdevelopmentX–inactivationisclonalunblancedor“skewed”XinactivationresultsinmanifestingheterozygotesParentalimprinting/genomicimprinting

(亲代印迹)

Genomicimprinting

isa

genetic

phenomenonbywhichcertain

genes

are

expressed

ina

parent-of-origin-specificmanner.Itisaninheritanceprocessindependentoftheclassical

Mendelianinheritance.Imprinted

alleles

aresilencedsuchthatthegenesareeitherexpressed

only

fromthenon-imprintedalleleinheritedfromthemother,orfromthenon-imprintedalleleinheritedfromthefather.Genomicimprintingisan

epigenetic

processthatinvolves

DNAmethylationand

histonemethylation

inordertoachieve

monoallelicgeneexpressionwithoutalteringthegeneticsequence.Theseepigeneticmarksareestablishedinthegermlineandaremaintainedthroughoutallsomaticcellsofanorganism.E.g.Prader-Willi

syndromewiththepaternaldeletionof15q11-13.

Angelmansyndromewiththematernaldeletionof15q11-13.GeneticHeterogeneity（遗传异质性）Geneticheterogeneity:Sameorsimilarphenotypesareactuallydeterminedbydifferentgenotypes.Maybeduetoallelicheterogeneity,locusheterogeneity,orbothAllelicheterogeneity:similarphenotypesarecausedbydifferentmutationsatthesamelocusLocusheterogeneity:similarphenotypesarecausedbydifferentgenes.Nearly1400differentmutationshavebeenfoundintheCFTRgene.Sometimes,differentmutationsresultinclinicallyindistinguishabledisorders.Inothercases,differentmutantallelesatthesamelocusproduceasimilarphenotypebutalongacontinuumofseverity.e.g.Allelicheterogeneitye.g.LocusheterogeneityAutosomaldominantAutosomalrecessiveX-linkedrecessiveMitochondrialCongenitalDeafness

Consanguineousmating(近亲婚配）

&Coefficientofkinship（亲缘系数）

Consanguinityisdefinedarbitrarilyasaunionofindividualsrelatedtoeachotherascloseasorcloserthansecondcousins.Thechancethatbothparentsarecarriersofamutantalleleatthesamelocusisincreasedsubstantiallyiftheparentsarerelatedandcouldeachhaveinheritedthemutantallelefromasinglecommonancestor,asituationcalledconsanguinity.Thus,consanguinityincreasesrecurrenceriskofveryrarerecessiveinheritancediseases.Coefficientofkinship

(Coefficientofrelationship,k亲缘系数)：Theprobabilitythatanytwoindividualsshareagivengeneatarandomlocusfromacommonancestor.Fancywayofsaying–howrelatedarethesetwopeople?Coefficientofkinship(k)

First-degreerelativesk(parent-childorI1-II1)=1/2k(sib-siborI