医学遗传学教学课件：Genetic Counseling and Risk Assessment Ethical Issues in Medical Genetics

GeneticCounselingandRiskAssessment

EthicalIssuesinMedicalGenetics

Determiningrecurrencerisks

Theprocessofgeneticcounseling

EthicalissuesinmedicalgeneticsOutlineTOMASTER:WhatisgeneticcounselingRisksestimationbyuseofconditionalprobabilitywhenalternativegenotypesarepossibleMajorethicalpolicyinmedicalgeneticsWhatisgeneticcounseling?Aprocessofcommunicationtoprovideinformationandsupporttofamiliesatriskforhaving,orwhoalreadyhave,memberswithbirthdefectsorgeneticdisease.Incommondisorders→givenbythefamilydoctor,thepediatricianortheobstetrician.RECENTLY,byGeneticCounselor.GeneticCounselor(GC)isahealthcareprofessionalwithamaster’sdegreeinhumangeneticsandcounseling.ThistrainingenablesGCstodiscusstechnicalgeneticinformationinpractical,usefulterms.Whoprovidegeneticcounseling?CommonindicationsPreviouschildwithgeneticdisorderFamilyhistoryofahereditaryconditionPrenataldiagnosisConsanguinityTeratogenexposureRepeatedpregnancylossorinfertilityNewlydiagnosedgeneticconditionbeforeundertakinggenetictestingandafterreceivingresultsAsfollow-upforapositiveresultGeneticcounselingcasemanagementCollectionofinformationFamilyhistoryMedicalhistoryTestand/oradditionalassessmentAssessmentPhysicalexaminationValidationorestablishmentofdiagnosisCounselingNatureandconsequenceofdisorderRecurrenceriskAvailabilityoffurtherorfuturetestingDecisionmakingReferraltootherspecialists,healthagencies,supportgroupsFollow-upContinuingclinicalassessmentPsychosocialsupportExampleMsWang–30yearoldfemale,screened(+)forDownsyndromeStep1:preassenssmentFamilyhistory:anyfamilymembermaybeaffectedbythesimilarillnesspedigreeMedicalhistory:especiallyforthesickindividual.MsWang’sbrother(wasbornnormal??)Assessment:mentalretardationwassuspected&moretestwillbeperformedStep2:counselingExplainMSSresultandDownsyndromeOptionsforfurtherdiagnosisDiscussiononfamilyhistoryBrother’scaseOptionstoclarifyingthesicknessExample

Test:brotherGeneticsdiseasesNogeneticcauseTest:MsWangcarrierNotcarrierTest:FetusDiscussionFetuskaryotypingExplanationExampleDeterminingrecurrencerisks

-----acentralconcerningeneticcounselingRiskestimationwhengenotypesarefullyknownbyuseofMendel’slaws

AutosomaldominantWhatistheprobabilitythatindividual3willbeaffected?123AaaaAutosomalrecessiveWhatistheprobabilitythatindividual5willbeaffected?12345AaAaX-linkedrecessiveWhatistheprobabilitythatthewomanwillhaveanaffectedson?Riskestimationbyuseconditionalprobabilitywhenalternativegenotypesarepossible

BayesiananalysisAmethodthattakesadvantageofphenotypicinformationinapedigreetoassesstherelativeprobabilityoftwoormorealternativegenotypicpossibilitiesandconditiontheriskonthebasisofthatinformation.ConditionalprobabilityFamilyAcarrierrisk50%IIIIII121212345FamilyBcarrierrisk3%IIIIII12123412345HowtocalculateactualriskusingBayes’theoremIIIIII123412345IIIIII123412345IIIIII123412345A:II-2isacarrier,buttheconsultanddidnotinheritedthemutantalleleB:II-2isacarrier,andtheconsultanddidinheritedthemutantalleleC:II-2isnotacarrierandtheconsultandcouldnothaveinheritedthemutantallelePriorprobabilitiesConditionalprobabilitiesJointprobabilitiesPosteriorprobabilities1/21/21/2(1/2)41/2(1/2)41/21411/2×(1/2)4×1/2=1/64

1/2×14×1=1/2

1/2×(1/2)4×1/2=1/64

1/641/64+1/64+1/2=1/341/641/64+1/64+1/2=1/34≈3%1/21/64+1/64+1/2=16/17PriorprobabilitythataFemaleinthepopulationisaCarrierofanX-linkedlethaldisorderH:thepopulationfrequencyoffemalecarriersAssume:HisconstantfromgenerationtogenerationThemutationrateinanyonegamete=μ,anditisthesameinmalesandfemales.Threewaysthatanyfemalecouldbeacarrier:Amutantallelefromacarriermother=1/2HAnewlymutantalleleontheXfromhermother=μAnewlymutantalleleontheXfromherfather=μH=(1/2×H)+μ+μH=4μConditionalprobabilityinX-linkedlethaldisordersA:III-1isanewmutationB:I-1isnotacarrier,II-1mustbetheproductofamaternalorpaternalnewmutationC:I-1andII-2arebothcarriersPriorprobabilitiesConditionalprobabilitiesuJointprobabilitiesu

4u×1/2×1/2=u

2u×1/2=u

IIIIII121212IIIIII2u121212IIIIII1/21212124u1/21/2Posteriorprobabilitiesu/3u=1/3u/3u=1/3u/3u=1/3TheriskthatII-1isacarrier:1/3+1/3=2/3TheriskthatIII-2isacarrier:2/3×1/2=1/3BayesianCalculationforMothersofIsolatedCasesofX-LinkedLethalDisordersII-1isacarrierII-1isnotacarrierPriorprobability4u1-4uConditionalprobability1/2uJointprobability4ux½=2u1xu=uPosteriorprobability2u/（2u+u）=2/3u/（2u+u）=1/3Thepenetranceis70%.Whatistheprobabilitythatindividual3willhaveanaffectedchild?123DisorderwithincompletepenetranceAaaaPriorprobability1/21/2Conditionalprobability1－7/10＝3/101Jointprobability1/2×3/10=3/201/2Posteriorprobability(3/20)/（3/20+1/2）=3/13(1/2)/（3/20+1/2）=10/13Theprobabilityis3/13×1/2×7/10≈8%.Individual3is30year-old.Whatistheprobabilitythatindividual3willbeaffected?123DisorderwithlateageatonsetProportionofpopulation(%)10090807060504030201001020304050607080Age(yr)AaaaPriorprobability1/21/2Conditionalprobability1－1/3＝2/31Jointprobability1/2×2/3=1/31/2Posteriorprobability(2/6)/（2/6+3/6）=2/5(1/2)/（2/6+3/6）=3/5Theprobabilityis40%.Inthispedigree,whatistheprobabilitythatindividualSisaffected?AaaaSⅠⅡⅢⅣⅢ-1isacarrierⅢ-1isnotacarrierPriorprobability1/43/4Conditionalprobability1/2×1/2×1/2=1/81Jointprobability1/4×1/8=1/323/4×1=3/4Posteriorprobability(1/32)/(1/32+24/32)=1/25(24/32)/(1/32+24/32)=24/25Shewillhaveanaffectedson:1/25×1/2=1/50X-linkedrecessiveWhatistheprobabilitythatthewomanMwillhaveanaffectedson?MThemotheris