医学遗传学英文版

CancerGeneticsMedicalGeneticsCancerisaclassofdiseasescausedbylossofcellcyclecontrol.CancerInanimals,cellnumbersareunderexquisitecontrolLossofthiscontrolleadstoproliferationofunwantedcellsCancerariseswhentheabovesituationreachesacertaindegreeCancer&TumorCancercellsaremalignanttumor(vs.benigntumor)cellsAllcancercellsareeventuallycapableofmetastasisCancerFamilyUnusuallylargenumbersofbloodrelativesdevelopcertainkindsofcancers.LynchCancerFamilySyndromeⅡ“FamilyG”:Italianfamily

WarthinAS.Hereditywithreferencetocarcinoma.Arch.Intern.Med.1913.12:546-555HauserIJ,WellerC.VAfurtherreportonthecancerfamilyofWarthin.Am.J.Cancer.1936.27:434-449LynchHT,KrushAJ.Cancerfamily'G'revisited:1895-1970.Cancer.1971.27:1505-1511LynchCancerFamilySyndromeⅡ“FamilyG”:Italianfamily

MIM114400LynchCancerFamilySyndromeⅡHNPCC:18q11-q12

Adenocarcinomasofthecolon“FamilyG”:Italianfamily

CarcinomaofendometriumGastriccancer,ovarycancer,breastcancerLi-FraumeniSyndromeStudiesbyLiandFraumeniledtofirstevidenceofinheritedpredispositiontocancer.(MIM151623)BreasttumorsSarcoma,leukemia,lungcancer,andadrenalcorticalcarcinomaCancerFamilyEarlierageofonsetMultiplecloserelativesaffectedMultipleprimarytumours/bilateraldiseaseMultipletumoursinspecificcancersyndromeInheritedCancerRetinoblastoma,RB(MIM180200)Retinoblastomaoccurssporadicallyinmostcases,butinsomefamiliesitdisplaysautosomaldominantinheritance.RetinoblastomaAraremalignanttumorofthedevelopingretinathatoccursinchildren,usuallybeforetheageoffouryears.Anabnormalappearanceofthepupilwhichreflectslightlikeacat'seye.RetinoblastomaAraremalignanttumorofthedevelopingretinathatoccursinchildren,usuallybeforetheageoffouryears.Anabnormalappearanceofthepupilwhichreflectslightlikeacat'seye.Someformsrepresentadeletionintheregion13q14.1-q14.2TwoMutationTheoryKnudson(1971)TwoMutationTheoryTwomutationsarerequired,oneineachcopyoftheRBgeneThefirstmutationispresentinthegermlineandthusinallcellsofthebodyForfamilialcasesThesecondsomaticmutationisnecessaryforinitiatingtumorformationInheritedcancerInitiationPromotionCloneOriginTheorySporadiccancerCloneOriginTheoryInitiationLossofHeterozygositymalignanttransformationRBLossofHeterozygosityRBrbgeneconversionWilms’TumorNephroblastoma(MIM194070)EmbryonickidneytumorAccountsfor3/4occurringbeforeagefour,90%beforetwenty.Inheritedcasesofnephroblastomadisplayautosomaldominantinheritance.Anoninvasivelesionwithapredictablelikelihoodofbecomingmalignant.Mostdisplayautosomaldominantinheritance.PrecancerousLesionFamilialPolyposisColiFPC(MIM175100)Averageonsetis25yearsoldAdenomatouspolyps,mostlycolorectalMinimum100polyps,average1,000polypsAPCgene(AdenomatousPolyposisColi)localizedtochromosome5q21100%willdevelopcancerwithin10to15yearsNeurofibromatosisNF1(MIM162200)Generallyincludesmultiplecafé-au-laitspots,cutaneousneurofibromasNF1gene(nervegrowthfactor)localizedtochromosome17q11.2Thepresenceofoneormoregeneticfactors,notnecessarilyabnormal,thatisassociatedwithanincreasedriskforthecancer.GeneticSusceptibilityFragilesiteChromosomeunstableImmunedeficiencyMetabolismofcarcinogenFragileSite

Ageneticdefectmakesthechromosomefragileandsusceptibletobreakageataspecificpoint.InheritableFragileSiteSuchfragilesitesshowhighexpressionandinheritedinaMendelianfashion.SusceptibletofolicacidsupplementsSusceptibleto5-BrdUsupplementsSusceptibletotelomycinsupplementsNon-inheritableFragileSiteSuchfragilesitesshowlowexpression.4q31FragileSite&CancerThelocationsoffragilesiteshavebeenshowntocorrelatewithsitesoftranslocationbreakpointsanddeletionscommonlyfoundincancer.——YunisJJ,1975ChromosomeUnstableChromosomeunstablecausedbyDNArepair-deficiencysusceptibletobreakageorrearrangement.BloomSyndrome,BSArareARdisorder(MIM210900)PossiblephenotypesNarrowfaceProminentnoseorearsImmunodeficiencyMorecancerprone“Butterflyrash”withskinsensitivitytosunHypo/hyperpigmentedskinlesionsBloomSyndrome,BSArareARdisorder(MIM210900)BloomSyndrome,BSArareARdisorder(MIM210900)CellularlevelGeneticinstabilitySisterchromosomeexchange(SCE)ExcessivenumbersofsomaticmutationsChromosomalaberrationsPossiblephenotypesBloomSyndrome,BSArareARdisorder(MIM210900)BloomSyndrome,BSArareARdisorder(MIM210900)BloomSyndrome,BSArareARdisorder(MIM210900)DNAhelicaseproteinofRecQfamilyCellularlevelPossiblephenotypesXerodermaPigmentosum,XPARdisorder(MIM278700)Inheritednucleotideexcisionrepair(NER)deficiencyXtremeskinsensitivitytoUVlightAbnormalskinpigmentationHighfrequencyofskincancersXerodermaPigmentosum,XPARdisorder(MIM278700)XerodermaPigmentosum,XPARdisorder(MIM278700)ImmuneDeficiencyAgammaglobulinemia,SwissType

SCID,Severecombinedimmunodeficiencydisorder

(“bubbleboy”syndrome)SCIDgene:Xq13,XR

(MIM300400)ImmuneDeficiencyADAdeficiency(MIM102700)Severecombinedimmunodeficiency(SCID)causedbymutationinadenosinedeaminasegeneinTcells.ADAgene:20q13.11,ADImmuneDeficiencyAIDSAcquiredimmunedeficiencysyndromeHIV(humanimmunodeficiencyvirus)MetabolismofCarcinogenAHH(MIM108330)ArylhydrocarbonhydroxylaseAHHinducibility(MIM108340)CYP1A1gene:15q22-q24ChromosomeTheoryBoveriT(1902)Abnormalfertilizationofseaurchineggsbytwospermcellscausesunequaldistributionofchromosomesinresultingdaughtercells.ChromosomeTheoryBoveriT(1902)Theunequaldistributionsofchromosomescouldbethecausalfactorsintumorformation.ChromosomeTheoryBoveriT&SuttonW(1903)ChromosomeTheoryBoveriT&SuttonW(1903)Tumorcellscomefromnormalcells.Tumorcellsaredefectivecellswithchromosomalabnormality.Thechromosomalaberrationsarethecausalfactorsintumorformation.ChromosomalAbnormalityCloneevolutionStemline&SidelineStemline&ModalnumberChromosomalAbnormalityNumericalabnormalityChromosomalAbnormalityStructuralaberrationStructuralAberrationPhchromosomeNowell&Hungerford,1960ChronicMyeloidLeukemia(CML)Rowley,1973Recognitionoft(9;22)t(9;22)(22pter→22q11::9q34→9qter)StructuralAberrationPhchromosomeStructuralAberrationPhchromosomeStructuralAberrationBurkittlymphoma(BL)t(8;14)(q24;q32)OncogeneAgenethatcausesnormalcellstochangeintocanceroustumorcells.1910,Rous,Roussarcomavirus(RSV)1963,Dulbecco,viruscanchangenormalcellintotumorcellTheNobelPrizeinPhysiologyorMedicine1975RenatoDulbecco"fortheirdiscoveriesconcerningtheinteractionbetweentumourvirusesandthegeneticmaterialofthecell"OncogeneAgenethatcausesnormalcellstochangeintocanceroustumorcells.1910,Rous,Roussarcomavirus(RSV)1963,Dulbecco,viruscanchangenormalcellintotumorcell1970,malignantconversioncausedbyretrovirus1970,Martin,v-src(viraloncogene,v-onc)1971,Dresberg,v-srcinRSVOncogeneLTRψGAGPOLENVV-srcLTRv-srcOncogeneAgenethatcausesnormalcellstochangeintocanceroustumorcells.1910,Rous,Roussarcomavirus(RSV)1963,Dulbecco,viruscanchangenormalcellintotumorcell1970,malignantconversioncausedbyretrovirus1970,Martin,v-src(viraloncogene,v-onc)1971,Dresberg,v-srcinRSV1976,Bishop,C-SRC(cellularoncogene,C-ONC)OncogeneLTRψGAGPOLENVV-srcLTRv-srcC-SRCOncogeneAgenethatcausesnormalcellstochangeintocanceroustumorcells.Proto-oncogene:Agenethatnormallydirectscellgrowth.CategoriesofOncogeneGrowthfactorSomecellsnormallyproducemitogensISI:Platelet-derivedgrowthfactor(PDGF)GeneticchangesmayenhancethisproductionormakeitcontinuousCategoriesofOncogeneGrowthfactorreceptorsReceptorGenesmaybemutatedsothatTheyareover-expressedBechangedtoacontinuouslyactivestateCategoriesofOncogeneProteinkinaseMembranouseffectsTyrkinaseCytoplasmiceffectsSer/ThrKinaseCategoriesofOncogeneSignal-transductionproteinRasfamilyGTP-bindingproteins(Gproteins)BoundtoGDP,RasproteinsareneutralinregardtomitotisBoundtoGTP,RasproteinssendsignalstothenucleusCategoriesofOncogeneTranscriptionfactorNucleartranscriptionFactoractivatingSRC,ABL,ROS,YESHRASKRASNRASMAPKKMAPKCYTOPLASMNUCLEUSSIS,INT2,HSTERBB1,FMS,ERBA,KITCytoskeletonSRC、ABL、ROS、YESCascadereactionMYCJUN,FOSDNAreplicationTranscriptionregulationEXTRACELLULARSchematicofOncogeneMechanismsofOncogeneActivationMutationPointmutations/deletions/insertionsMostcharacterizedintranscription-regulatingsequence(TRS),frequentinRasMechanismsofOncogeneActivationMutationVirus(promoter)insertionLTRofretrovirusMechanismsofOncogeneActivationMutationVirus(promoter)insertionResultsfromseveralroundsofunscheduledDNAsynthesisoccurringduringasinglecellcycleGeneamplificationHomogeneouslystainingregion(HSR)Doubleminutes(DMs)DoubleMinutesMechanismsofOncogeneActivationMutationVirus(promoter)insertionGeneamplificationChromosomalrearrangementTranslocations;inversionsGeneActivationTranscriptionalactivationBurkittlymphoma75％:t(8;14)(q24;q32)16％:t(8;22)(q24;q11)9％:t(2;8)(q12;q24)14q32:IGH8q24.1:C-MYC22q11:IGL2q12:IGKGeneFusionCodesformosaicproteinPhchromosome(CML)t(9;22)(q34;q11)9q34.1:C-ABL22q11:breakpointclusterregion,BCR1BCR1-ABL:8.5kbmRNA,210kDpr.TumorSuppressorGeneAnti-oncogeneRecessiveoncogeneAclassofgenesthatareinvolvedinthenegativeregulationofnormalgrowth.PDGFREGFRCyclinDCDK4,6CyclinECDK2E2FGSG2MG0p16,p15p53p21p27SchematicofCellCyclepRBPDGFREGFRCyclinDCDK4,6CyclinECDK2E2FGSG2MG0p16,p15p53p21p27SchematicofCellCyclepRBNormalcellulargenesthatinhibitstumorinvasionandprogression.TumorMetastasisSuppressorGenenm23H1MechanismsofOncogenesisMonoclonalorigintheoryTwomutationtheoryMultisteponcogenesistheoryPainterTS.Studiesinmammalianspermatogenesis.II.Thespermatogenesisofman.JExpZool.1923;37:291-336DarkAgesHsuTC.Mammalianchromosomesinvitro.I.Thekaryotypeofman.JHered.1952;43:167-172TjioJH,LevanA.Thechromosomenumberofman.AmJObstetGynecol.1956;130:723-724HypotonicPeriodDarkAgesTrisomyPeriodLejeuneJ,etal.Etudedeschromosomessomatiquesdeneufenfantsmongoliens.G.R.Acad.Sciences.1959;248:1721-1722FordCE,etal.Asexchromosomalanomalyinacaseofgonadaldysgenesis(Turner'ssyndrome).Lancet.1959;1:711-713JACOBPA,etal.AcaseofhumanintersexualityhavingapossibleXXYsexdeterminingmechanism.Nature.1959;183:302-303.HypotonicPeriodDarkAgesBandingEraCasperssonT,etal.Differentialbandingofalkylatingfluorochromesinhumanchromosomes.ExpCellRes.1970;60:315-319HypotonicPeriodDarkAgesTrisomyPeriodMolecularEraPardueML,etal.MolecularhybridizationofradioactiveDNAtotheDNAofcytologicalpreparations.Proc.Natl.Acad.Sci.USA.1969;64:600-604PinkelD,etal.Cytogeneticanalysisusingquantitative,high-sensitivity,fluorescencehybridization.Proc.Natl.Acad.Sci.USA.1986;83:2934-2938.HypotonicPeriodDarkAgesBandingEraTrisomyPeriodKaryotypeanalysis:

arrangingthechromosomesofacellintoakaryotype,thenanalysisandcomparewithDenversystem.DenverSystemThekaryotypeisaphotographofallofthechromosomesofanindividualcell;thetermcoversthenumber,relativesizesandstructureofthechromosomes.Chromosomecanbedistinguishedbytherelativesizesandthepositionofthecentromere.Metacentric(1,3,16,19,20)Submetacentric(2,4-12,17,18,X)Acrocentric(13,14,15,21,22,Y)DenverSystemDenverSystemBandingPatternBand:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.Bandingpattern：treatedwithchemicaldyes,24typesofchromosomesappearitsuniquestriationsindividually.Q-banding：QMG-banding：pancreatin＋GiemsaBandingPatternBand:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.R-banding：treatedspecimen＋GiemsaorAcridineOrangeBandingPatternQ-banding：QMG-banding：pancreatin＋GiemsaBand:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.C-banding：Ychromosome,centromere,secondaryconstrictionBandingPatternR-banding：treatedspecimen＋GiemsaorAcridineOrangeQ-banding：QMG-banding：pancreatin＋GiemsaBand:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.T-banding：endingofchromosomeBandingPatternC-banding：Ychromosome,centromere,secondaryconstrictionR-banding：treatedspecimen＋GiemsaorAcridineOrangeQ-banding：QMG-banding：pancreatin＋GiemsaBand:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.N-banding：AgNO3＋Giemsa,NORT-banding：endingofchromosomeBandingPatternC-banding：Ychromosome,centromere,secondaryconstrictionR-banding：treatedspecimen＋GiemsaorAcridineOrangeQ-banding：QMG-banding：pancreatin＋GiemsaBand:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.LandmarkXpXqRegionBand112212345678Xq28BandingPatternDevelopment1.Highresolutionbandingchromosome(HRBC)FISH(fluorescenceinsituhybridization)DNAfiber-FISHChromosomePaintingCGH(comparativegenomichybridization)3.MolecularcytogeneticsDevelopment2.Microcytogenetics1.Highresolutionbandingchromosome(HRBC)HeteromorphismBandingpatternpolymorphismChromosomeheteromorphismsarenormalvariationsintheappearanceofchromosomes.BeinheritedinaMendelianfashionConstitutiveheterochromatinNotchromosomalabnormalityinclinicalHeteromorphismBandingpatternpolymorphismChromosomallengthSatelliteSecondaryconstrictionPolymorphismofQ,G,CbandingChromosomalAberrationNumericalAbnormalityStructuralAberrationNumericalAbnormalityHaploid:22+X,22+YDiploid:44+XX,44+XYNumericalAbnormalityVariationinchromosomenumbercantake2forms:Euploid:thatwhichinvolveswholesets(genomes)ofchromosomesAneuploid:thechromosomenumberisnotanexactmultipleofthehaploidnumberEuploidTriploid:thecellwhichhas3sets(genomes)ofchromosomes——3n＝69NumericalAbnormalityNumericalAbnormalityEuploidTriploid:thecellwhichhas3sets(genomes)ofchromosomes——3n＝69Tripolarspindle

Diandry:

fertilizationof1oocyteby2spermatozoa

Digyny:non-expulsionofthe2ndpolarbodyNumericalAbnormalityEuploidTriploid:thecellwhichhas3sets(genomes)ofchromosomes——3n＝69Euploid

——polyploidTetraploid:thecellwhichhas4sets(genomes)ofchromosomes——4n＝92

EndoreduplicationNumericalAbnormalityEndoreduplicationDiplochromosome

DiplochromosomeEuploid

——polyploidTetraploid:thecellwhichhas4sets(genomes)ofchromosomes——4n＝92

EndoreduplicationNumericalAbnormality

EndomitosisBefoundmorecommonlythanEuploid.Hypodiploid:lessthanthenormal2nnumberofchromosomesNumericalAbnormalityAneuploidHyperdiploid:morethanthenormal2nnumberofchromosomesMonosomy:isthepresenceofonlyonecopyofanychromosomeLossofautosomesisnottoleratedTurnersyndrome:45,XNumericalAbnormalityAneuploidHypodiploidBefoundmorecommonlythanMonosomyTrisomy

ofsexchromosomeismorecommonlyNumericalAbnormalityAneuploidHyperdiploidTrisomy:isthepresenceofonlythreecopyofanychromosomeMeioticnon-disjunctionMitoticnon-disjunctionChromosomenon-disjunctionChromosomelossNumericalAbnormalityMechanismofAneuploidThe

BreakageandtheRejoinafterbreakagearethebasisofchromosomalstructuralaberration.ChromosomalrearrangementRearrangementchromosomeStructuralAberrationShortsystemDetailedsystemTerminalDeletionStructuralAberration4q27InterstitialDeletionStructuralAberration4q134q25ParacentricInversionStructuralAberration4q134q24PericentricInversionStructuralAberration4p144q21StructuralAberrationPericentricInversionStructuralAberrationPericentricInversionInversionloopStructuralAberrationPericentricInversionStructuralAberrationPericentricInversionInversionloopStructuralAberrationPericentricInversionRingChromosomeStructuralAberration2q312p21RingChromosomeStructuralAberration2q312p21p21q31RingChromosomeStructuralAberrationRingChromosomeStructuralAberrationReciprocalTranslocationStructuralAberration4q2520q12StructuralAberrationReciprocalTranslocationStructuralAberrationReciprocalTranslocationABCDFour-wayjunctionStructuralAberrationReciprocalTranslocationRobertsonianTranslocationStructuralAberrationStructuralAberrationRobertsonianTranslocationWholeArmTranslocationStructuralAberrationComplexTranslocationStructuralAberrationIsochromosomeStructuralAberrationIsochromosomeStructuralAberrationDicentricChromosomeStructuralAberration6q2211p15DirectInsertionStructuralAberrationInverseInsertionStructuralAberrationChromosomeDiseaseinClinicalClinicalfeatureThegeneralfeaturesinautosomeabnormalitiesareatriadofgrowthretardation,mentalretardation,andspecificsomaticabnormalities.Changeofsexchromosomealsohavetheabnormalitiesandmalformationsofinternalorexternalgenitalorgans.DownSyndrome(trisomy21syndrome)ChromosomeDiseaseinClinicalCharacteristicsGrowthretardationVaryingdegreesofmentalretardationFlattenedfaceUpwardslantingoftheeyeswithepicanthalfolds1in600~800newbornsChromosomeDiseaseinClinicalDownSyndrome(trisomy21syndrome)1.Trisomy

——

95%,47,XX(XY),＋21Causedbynon-disjunctionofchromosome21,correlatedwithageofmother.ChromosomeDiseaseinClinicalDownSyndrome(trisomy21syndrome)Karyotypeofaffected：46,XX(XY),－14,＋t(14q21q)2.Mosaic

——

2%~4%,46/473.UnbalancetranslocationKaryotypeofbalancecarrier：45,XX(XY),－14,－21,＋t(14q21q)ChromosomeDiseaseinClinical1.Trisomy

——

95%,47,XX(XY),＋21DownSyndrome(trisomy21syndrome)1in4000~5000newbornsEdwardsSyndrome(trisomy18syndrome)CharacteristicsGrowthretardationMentalretardationCongenitalheartdiseaseRocker-bottomfeetfixedflexiondeformityofthefingersChromosomeDiseaseinClinicalChromosomeDiseaseinClinical1in4000~5000newbornsEdwardsSyndrome(trisomy18syndrome)1in5000~7000newbornsPatauSyndrome(trisomy13syndrome)CharacteristicsVaryingdegreesofmentalretardationCleftlip&CleftpalatePolydactyly(postaxial)EquinovarusChromosomeDiseaseinClinical1in50000newborns5p－

Syndrome(CatCrysyndrome)CharacteristicsRound,moon-shapedface“Cryofthecat”VaryingdegreesofmentalretardationLowsetearsChromosomeDiseaseinClinicalTurnerSyndrome(45,X)1in2500livebornfemalesCharacteristicsShortstature&WebbedneckOvariandysgenesis,primaryamenorrhea,infertilityAbsenceofsecondarysexcharacteristicsUnderdevelopedbreasts;widenipplesChromosomeDiseaseinClinicalTrisomyXsyndrome(47,XXX)1in1000livebornfemales1in250psychopathoffemalesTwoofthethreeXchromosomesareinactivated.ChromosomeDiseaseinClinical1in800malesTallwithdisproportionatelylongarms/legsKlinefeltersyndrome(47,XXY)1in100mentallyretardedmales1in10infertilemalesPoorlydevelopedsecondarysexcharacteristicsTesticulardysgenesisChromosomeDiseaseinClinical1in750~1500malesTallstatureXYYsyndrome(47,XXY)1

in30maleprisonpopulationsPredispositiontoviolent,criminalbehavior＞180cm:1/200＞190cm:1/30＞200cm:1/10ChromosomeDiseaseinClinical1in1250malesFragileXchromosomesyndrome(FraX)CharacteristicsShowmildtoseverementalretardationLarge,protrudingearsEnlargedtestesNarrowfacewithaprominentchinBehavioralproblemsChromosomeDiseaseinClinicalFISHFISHFISHX染色體Y染色體13號染色體18號染色體21號染色體BackFISHDNAfiber-FISH3cosmidfromMHClocus35～40Kb/cosmidBackChromosomePaintingChromosomePaintingBackChromosomePaintingCGHCGHCGH

AdvantagesWholegenomein1experimentNoneedtoculturetumorcellsSensitivedetectionofgeneamplification

DisadvantagesLimitedresolution(~10Mbdel/dup)LaboriousOnlygainsandlosses/nobalancedrearrangementsNoinformationonthenatureoftheaberrationsRetrospectiveanalysisBackCGHMeioticNon-DisjunctionMeioticnon-disjunctionarisesfromfailureofpairedhomologouschromosomesorsisterchromatidtodisjoinatmeioticanaphase.2NNN＋1N－12N＋12N＋12N－12N－1N＋1N＋1N－1N－1MeioticNon-Disjunction2N2N2N＋12N－12NNNNNN－1N＋1Primarynon-disjunctionPrimarynon-disjunctionisthefailureofchromosomesorsisterchromatid

toseparateinmeiosis.Thegametethushastwocopiesofachromosome.Fertilizationaddsanothercopytogiveatotalof3copies.Secondarynon-disjunctionTrisomyoffspringarisefromsegregationatmeiosisofanalready-trisomyparent.MeioticNon-DisjunctionBackMeioticNon-Disjunction2N+1N2N2N2N＋12N＋1NN＋1NNN＋1N＋1MitoticNon-DisjunctionMitoticnon-disjunctionarisesfromfailureofsisterchromatidstodisjoinatmitoticanaphase.2N2N2N2N2N2N－12N＋12N2N－12N＋147/45Mosaic46/47/45MosaicBackClinicalDiagnosisHistorytakingPhysicalexaminationOtherexaminationPedigreeanalysisFamilyhistoryMaritalhistory:marriageableage,timesofmarriage,consanguineousMarriageChildbearinghistory:ChildbearingAge,

NoofChildren,abortion,fetaldeath,pregnanthistory,exposureofteratogen,ageofonsetHistoryTakingSeparately

SpecialistsPhysicalExaminationClinicalchemistryRadiologySupersonicsKaryotypeanalysisMoleculargeneticsOtherExaminationPedigreeAnalysisMendelianinheritanceNon-MendelianinheritanceOthersCytogeneticsFragilesiteInsituhybridizationCytogeneticsGrowthretardation&MentalretardationBalancedtranslocation&MosaicAffectedinfamilyMultipleabortionwomanandherhusbandInfertilityAdvancedmaternalageInternal/externalgenitalmalformationClinicalChemistryPhenylketonuria,PKUⅠEnzymeactivityPAHLiverBloodsampleBacillussubtilisGuthrietestFeCl3PhenylpyruvicacidGreenNewbornScreeningGeneDiagnosisDetectionofgeneticdisordersbyDNAanalysisGeneDiagnosisPathwayMolecularhybridizationPolyperasechainreaction(PCR)MendelianInheritanceAutosomaldominantdiseasesPedigreecharacteristicsInfluencingfactors

PenetranceExpressivitySexPleotropyMendelianInheritanceAutosomaldominantdiseasesPedigreecharacteristicsInfluencingfactors

EnvironmentalfactorsSomaticmutationDynamicmutationModifiergeneMendelianInheritanceAutosomalrecessivediseasesPedigreecharacteristicsInfluencingfactors

GeneticheterogeneityGeneticcompoundDoubleheterozygoteUniparentaldisomyMendelianInheritanceX-linkedrecessivediseasesPedigreecharacteristicsInfluencingfactors

LyonizationRecurrentmosaicMendelianInheritanceX-linkeddominantdiseasesPedigreecharacteristicsInfluencingfactors

LyonizationMendelianInheritanceY-linkeddiseasesHolandricinheritanceBackMendelianInheritancePartialsex-linkedPseudoautosomalregionX-linkedorY-linkedNon-MendelianInheritanceMitochondrialdisorderReplicativesegregationMatrilinealinheritanceHeteroplasmy&HomoplasmyDegenerativediseasesNon-MendelianInheritancePolygenicDiseaseHeritabilityCarter-effectBackNon-MendelianInheritanceGeneticImprintingNon-MendelianInheritanceDynamicmutationATGTAACGGFraXFraXE11BCAGGlnHDSCA1DRPLAMJDSBMAGAAFRDACGGXF16ACTGDMNon-MendelianInheritanceUniparentaldisomyAR&Growthretardation,mentalretardationAR→dominantinheritanceX-linked

→fathertosonBalancedtranslocation&birthdefectSex-influencedinheritanceSex-limitedinheritanceNon-MendelianInheritanceSexNon-MendelianInheritanceModifiergeneBackMolecularHybridization-+SouthernBlotPathologicMutationSicklecellanemia(HbS):code5~7

A

A

A

S

S

SMstⅡ:CCTNAGG1.2Kb

0.2Kb1.40Kb1.20Kb0.20Kb

A:CCTGAGGAG

S:CCTGTGGAGNeurofibroma,NF1RFLPⅠⅡⅢ1212345678123456784.7kb3.0kbLinkageAnalysisHaplotypeAnalysisAsetofcloselylinkedgeneticmarkerspresentononechromosomewhichtendtobeinheritedtogether(noteasilyseparablebyrecombination).HaplotypeAnalysis5.6Kb5.2Kb4.2Kb4.0KbHindⅢPKU，AR12ⅠⅡ123SphⅠ11.0Kb9.7Kb7.0KbBackASOHybridizationPKU,ARNormalprobeMutationprobe1.2kb0.2kbSicklecellanemia(HbS):code5~7MstⅡ:CCTNAGG

A:CCTGAGGAG

S:CCTGTGGAGPCR-RFLPPCR-RFLPPCR-ASOPKU,ARNormalprobeMutationprobe12345abPCR-SSCPsinglestrandconformationpolymorphismPCR-SSCPGAA→GAGTGT→TATCTC→CACPCR-DGGEDenaturinggradientgelelectrophoresisPCR-DGGE1234567891011192428333742RecombinationDNATechniqueTechniquesforjoiningDNAmoleculesinvitroandintroducingthemintolivingcellswheretheyreplicate.InsertspecificDNAintovectorCloneinhostcellsCloningIsolateclonedDNAforeignDNAbacterialcellSchematicofrecombinationDNAtechniquevectorrestrictionendonucleaseforeignDNAbacterialcellSchematicofrecombinationDNAtechniqueligasevectorrestricti