单基因遗传病-高级遗传2014.

单基因遗传病SinglegenedisordersMonogenicdisordersEtiologyofdiseases.Foranyconditiontheoverallbalanceofgeneticandenvironmentaldeterminantscanberepresentedbyapointsomewherewithinthetriangle.ClassificationofGeneticDisordersSinglegenedisordersarecausedbydefectsinoneparticulargene,andoftenhavesimpleandpredictableinheritancepatterns.Theyaffectabout1percentofthepopulationasawhole.Epigeneticmodifications？Otherreasons?•Multifactorial(common)Variantsingenescausingalterationoffunction“Environmental”influencesactonageneticpredispositiontoproducealiabilitytoadisease.Oneormoreorgansystemaffected.Personaffectedifliabilityaboveathreshold.•Singlegene(1%liveborn)Mutationsinsinglegenes(oftencausinglossoffunction)Dominant/recessivepedigreepatterns(Mendelianinheritance).Canaffectstructuralproteins,enzymes,receptors,transcriptionfactors.•Chromosomal(0.6%liveborn)Thousandsofgenesmaybeinvolved.Multipleorgansystemsaffectedatmultiplestagesingestation.Usuallydenovo(trisomies,deletions,duplications)butcanbeinherited(translocations).Classificationofgeneticdisorders+environmentMale•Mitochondrial•Somaticmutations(cancer)Singlegenedisorders:disordersinwhichinheritanceisduetoasinglemutantgene1.Mendelianinheritance2.Genesareunitsofheredity,basedinDNA3.Phenotype(physicalorfunctionalabnormalities)Genotype(DNAchange)4.AutosomalvsX-linkeddeterminedbywhethertheresponsiblegeneiscarriedononeoftheautosomalchromosomesorontheXchromosome5.DominantvsRecessive,basedonphenotypicexpressionRecessiveHomozygoteswithtwocopiesofthealteredgeneareaffectedDominantHeterozygoteswithonecopyofthealteredgeneareaffectedX-linkedrecessiveMaleswithonecopyofthealteredgeneontheX-chromosomeareaffectedMaleSinglegenedisorders-Highriskstorelatives-Dominant/recessivepedigreepatterns-Someisolatedcasesduetonewdominantmutations-Structuralproteins,enzymes,receptors,transcriptionfactorsI:1I:2II:1II:2II:3II:5II:6II:8III:1III:2IV:11212341ⅠⅡⅢCharacteristicsofsinglegeneinheritanceAutosomalDominantvertical(successive),riskofaffectedoffspring50%(bothsex)AutosomalRecessivehorizontal,multiplesibsaffected,usuallyonegeneration,consanguinity(+)riskofaffectedoffspring25%,carrier50%X-linkedDominantdaughtersofaffectedmales(+),sonsofaffectedmales(-),affectedfemalestransmitthedisordertooffspringofbothsexes,riskofaffectedoffspring50%,buttwiceasmanyaffectedfemalesasaffectedmales(nomaletomale)X-linkedRecessivemalesthroughcarrierwomen,malesaffectedalmostexclusively,femalesaffectedonlywhenaffectedfatherandcarriermotherorwithskewedX-inactivationY-linkedmalesaffectedCharacteristicsofAutosomalDominantinheritance1.Thephenotypeusuallyappearsineverygeneration,eachaffectedpersonhavinganaffectedparentExceptions:(1)freshmutation(2)thedisorderisnotexpressedorisexpressedonlysubtlyinapersonwhohasinheritedtheresponsiblegene.2.Anychildofanaffectedparenthasa50percentriskofinheritingthetrait3.bothmalesandfemalesareaffectedina1:1ratioAutosomaldominanceinheritance(AD)Pedigreeshowingtypicalinheritanceofaformofprogressivesensorineuraldeafness(DFNA1)inheritedasanautosomaldominanttraitCharacteristicsofAutosomalRecessiveInheritance1.AnautosomalRecessivephenotype,typicallyisseenonlyinthesibshipoftheproband,notinparents,offspring,orotherrelatives.2.bothsexesareaffectedwithequalfrequencyataratioof1:13.Parentsofanaffectedchildareasymptomaticcarriersofmutantalleles.heterozygousparentshaveariskof25%ofaffectedoffspring4.Theparentsoftheaffectedpersonmayinsomecasesbeconsanguineous.Thisisespeciallylikelyifthemutantgeneisrareinthepopulation.AutosomalRecessiveInheritance(AR)CharacteristicsofX-linkedDominantInheritance1.Theincidenceofthetraitismuchhigherinfemalesthaninmales(abouttwice),butaffectedfemalestypicallyhavemilder(variable)expressionofthephenotype.2.AffectedmaleswithnormalmateshavenormalsonsandAffecteddaughters.3.BothmaleandfemaleoffspringofAffectedfemalehavea50percentriskofinheritingthephenotype.4.Thepedigreepatternisthesameasautosomaldominantinheritance.X-linkedDominantInheritance(XD)CharacteristicsofX-LinkedRecessiveInheritance1.Theincidenceofthetraitismuchhigherinmalesthaninfemales.2.Thegeneisordinarilynevertransmitteddirectlyfromfathertoson(male-to-male),butitistransmittedbyanaffectedmaletoallhisdaughters.3.AcarrierFemaleforanX-chromosomalmutationhasariskof50%Foranaffectedson.4.Thegenemaybetransmittedthroughaseriesofcarrierfemales;affectedmalesinheritthemutantallelefromthemotheronly5.Heterozygousfemalesareusuallyunaffected,butsomemayexpresstheconditionwithvariableseverityasdeterminedbythepatternofXinactivationX-linkedRecessiveInheritance(XR)Y-linkedinheritanceGene:YA（mutantallele）YaGenotype:XYAXYaholandricinheritance(全男性遗传)male-to-maleY-linkedinheritanceSinglegenedisorders1.HuntingtonDisease2.MyotonicDystrophy3.HereditaryMotorSensoryNeuropathy(HMSN)4.Neurofibromatosis5.Marfansyndrome6.CysticFibrosis7.SpinalMuscularAtrophy(SMA)8.DuchenneMuscularDystrophy9.HemophiliaSomaticmosaicismandsinglegenedisordersMosaicism:referstoamixtureofcellsofdifferentgeneticcompositioninoneindividual.Whenthegenotypeofonezygoteisalteredbychromo