美国遗传咨询模式及经验

美国遗传咨询模式及经验报告提纲遗传咨询的发展和定义遗传咨询的操作内容，对象和原则遗传咨询师的培养及需具备的素质美国遗传咨询师的状况及资源从美国遗传咨询病例看遗传咨询的复杂性讨论如何开展中国的遗传咨询服务遗传咨询因需而生SheldonC.ReedPhDcoinedtheterm“geneticcounseling”soonafterhejoinedtheDightInstituteforHumanGeneticsattheUniversityofMinnesota.TheDightInstitutehadinitsmissiontoprovidecoursesandpubliclecturesabouthumangenetics,toparticipateinresearch,andtobeavailableforconsultationaboutquestionsrelatedto

human

genetics. IntheyearsthatDr.ReedwasattheDightInstituteitisestimatedthatherespondedtoover4,000such

questions.Fromthelate1940’stothemid1950’s,Dr.Reedattemptedtodescribethenatureofthegeneticquestionsandtheuniqueresponsesthatemerged.InaseriesofmeetingsandpublicationsoftheDightInstitute,Dr.Reedbegantointroducethetermgeneticcounseling.In1955,hepresentedtheconceptatthefirstInternationalCongressonHumanGenetics

in

Copenhagen. Also,

inthatsameyear,hisclassicwork,"CounselinginMedicalGenetics"was

published.遗传咨询因需而生MelissaRichterPhDmustbecreditedwiththeideaofgeneticcounselorprofessionals.MelissaRichter,anSarahLawrenceCollege(SLC)graduatewhotaughtbothpsychologyandbiologybeforebecomingDirectorofSLC’sCenterforContinuingEducation,sawagreatopportunityinthischallenge.“Inthelate1960’s,aprofessoratSLC,BronxvilleNYsensed

theneedforanewtypeofprofessional,oneconversantwiththemanifestations

ofgeneticdiseaseasweretechniquesofpsychosocialsupport”(SLC).Thisvisionevolvedtotheestablishmentofthefirstgeneticcounselingtrainingprogram.By1979,theprofessionofgeneticcounselorswasreadytoestablishtheNationalSocietyofGeneticCounselors(NSGC).TheNSGCistheleadingvoice,authority,andadvocateforthegeneticcounselorprofession.ManypracticinggeneticcounselorsinNYShadcriticalleadershiproles.Tolearnmore:HeimlerA.AnOralHistoryoftheNationalSocietyofGeneticCounselors.JGenetCouns.1997September;6(3):315-336

andRollnickB.theNationalSocietyofGeneticCounselors:AnHistorical

Perspective.BirthDefectsOrigArticSer.

1984;20(6):3-7USin1968=Todayin

ChinaDiagnosis>>counselingMelissaRichter,

PhDMemototheDeanofSarah

LawrenceCollege-

1968遗传咨询因需而生遗传咨询在美国的早期发展美国五十年代有了遗传咨询概念，在六十年代就呼吁培养专门的遗传咨询师。七十年代初开始培训班并随后成立了专门的委员会。七十年代末成立了全国范围的美国遗传咨询师学会（National

Society

ofGeneticCounselors，

NSGC）1975

ASHG

Definition

of

Genetic

counseling(Ad

Hoc

Committee

on

Genetic

Counseling)Geneticcounselingisacommunicationprocess

whichdealswiththehumanproblemsassociatedwiththeoccurrenceorriskofoccurrenceofageneticdisorderin

a

family. Theprocessinvolves

anattemptbyoneormoreappropriatelytrained

persons

tohelptheindividualorfamily

to…..1)Comprehendthemedicalfacts

includingthediagnosis,probablecourseofthedisorder,andtheavailable

management,2)appreciatetheway

hereditycontributestothedisorderandtheriskofrecurrence

inspecifiedrelatives,3)understandthealternatives

fordealingwiththeriskofrecurrenceinspecified

relatives4)chooseacourseofactionwhichseemstothemappropriateintheirviewoftheirrisk,theirfamilygoals,andtheirethicalandreligiousstandardsandactinaccordancewiththat

decision5)Makethebestpossibleadjustment

tothedisorderinanaffectedfamilymemberand/ortotheriskofrecurrenceofthat

disorder.1975

ASHG

Definition

of

Genetic

counseling(Ad

Hoc

Committee

on

Genetic

Counseling)NSGC对遗传咨询的界定遗传咨询是一个帮助人们理解和适应遗传因素对疾病的作用及其对医学、心理和家庭影响的沟通过程。包括通过家族史，

病史来评估疾病在家庭成员中的发生及其再发风险；提供有关疾病的遗传模式、实验室检测、治疗处理及预防的教育，并提供与疾病相关的各种可以求助的渠道及参与研究的可能性；辅导促进知情选择和对所患疾病及其再发风险的逐步认知和接受。遗传咨询师的定义FirstGeneticCounselorDefinition

2001“Geneticcounselingisadynamic

psycho-educationalprocesscenteredongenetic

information”Goaltofacilitateclient’sabilitytousegeneticinformationinapersonallymeaningfulwaythatminimizespsychologicaldistressandincreasespersonal

control遗传咨询是以遗传学信息为核心的一个动态的心理教育过程遗传咨询师的作用就是能够使用遗传学知识，以个人灵活的方式减少患者的紧张和增加自我的控制信心。NSGC对遗传咨询师的界定遗传咨询师是经过独特专业训练，具硕士研究生学位，并在医学遗传学和咨询方面有经验的医护人员。遗传咨询师是健康管理医疗小组的成员，提供风险评估，并对有一定风险或已经诊断为某种遗传病的个人和家庭提供教育和支持。遗传咨询也提供基因检测报告解释，并为患者的利益提供支持和倡导。遗传咨询的特殊内涵Two-way

interaction

(双向互动)Process

–takes

time

(需要花时间）Patient

autonomy

in

decision-making

（自愿原则）will

vary

based

on

personal,

family

and

cultural

contextsFamilywideimpactdifferentfromotherkindsofdiseases

（家庭广泛受影响）Psychotherapeutic

component

（心理治疗的成分）Appropriately

trained

individuals（需要培训良好的人员）With

special

knowledge/skills

not

found

in

othermedical/psychological

interactions遗传检测和遗传咨询的临床操作构架临床医生遗传检测病人及家属遗传咨询专业培训资格认证遗传咨询是遗传检测不可缺少的一个组成部分遗传咨询师在诊断实验室中的作用检测项目的设计开发(充分了解基因与疾病的相关性）变异的数据分析及解释(序列及拷贝数变异的临床意义)起草报告与用户（医生）沟通遗传咨询师在遗传门诊的作用病人临床评估家史/家谱图/遗传模式评估与临床医生沟通跟临床医生及病人解释实验室报告，咨询建议下一步医疗处理传统的遗传咨询对象遗传筛查阳性者高龄孕妇，即孕妇年龄达到或者超过35岁曾怀有遗传病的胎儿或者生育过有遗传病的孩子父母之一是遗传病患者有反复发生的自发性流产或不孕不育病史的夫妇；超声异常父母是遗传病基因携带者；夫妇之一有遗传病家族史；近亲婚配；生长异常外环境致畸物接触史；肿瘤和遗传因素明显的常见病；遗传咨询对象的扩展Frompatientto

non-patientFromhigh-risktogeneral

riskFromMendeliangeneticconditionstocomplex

disordersFromdiseasesto

traits遗传咨询必须遵循的伦理、道德原则和法律自愿的原则平等的原则教育咨询者原则公开信息的原则非指导性的咨询原则关注咨询中的心理、社会和情感影响尺度信任和保护隐私的原则遗传诊断的伦理、道德问题与遗传诊断相关的法律问题遗传伦理委员会An

yu针对病人及家属的遗传咨询我的孩子得了什么病我的孩子是怎么得这个病的这个病是遗传的吗？家里其他人的风险是多大，谁需要做检测？会传给下一代吗？如何避免此病再发？这个病的预后如何，孩子长大了会怎样？能正常上学吗？

生活能自理吗？能生育吗？Shorten

longevityRequirechronic

hospitalizationRequirecostly

treatmentsAffect

mental

orphysical

development,

including

the

ability

to

engageinnormal,independentdaily

activitiesImpair

reproductive

performance,

including

possible

infertility这个病有治吗？

有什么治疗的办法？哪里可以找到更多有关的信息和得到帮助。做什么检测可以确认诊断？检测的有效性及局限性？检测所带来的其他问题？知情同意解释检测的过程及期待知情同意的要点明确需要提供的血液或其他生物组织及设计的（很小的）风险明确检测的具体项目及目的检测结果预期阴性结果，阳性结果的可能性及含义报告对象，

隐私保密后续如何参加研究IthasbeenexplainedtomeandIunderstand

that:Thetest(s)isspecific

for

.Abloodspecimenwillbeobtainedfrommeand/ormembersofmy

family.ThisbiologicalspecimenwillbeusedforthepurposeofdeterminingwhetherIandmembersofmyfamilyarecarriersofthediseasegene,orareaffectedwith,oratincreasedrisktosomedaybeaffectedwiththisgeneticdisease.Inmanycasesagenetictestdirectlydetectsanabnormality.Moleculartestingmaydetectamutation(changeintheDNA).Cytogenetictestingmayidentifywhetherthereisextra,missingorrearrangedgeneticmaterial.Biochemicalmethodsaresometimesusedtolookatabnormalitiesinthebiologicalproduct(s)ofthegene,suchasprotein,enzymeorlipid.Mosttestsarehighlysensitiveandspecific.However,sensitivityandspecificityaretestdependent.Theaccuracyofthetestdependsoncorrectfamilyhistory.AnerrorindiagnosismayoccuriftheactualbiologicalrelationshipsofthefamilymembersinvolvedinthisstudyarenotasIhavedescribed.Anerrorindiagnosisinafamilymembermayleadtoanincorrectdiagnosisforotherrelatedindividuals.Inaddition,testingmayinadvertentlyrevealnon-paternityor

consanguinity.ApositiveresultisanindicationthatImaybepredisposedtoorhavethespecificdiseaseor

condition.Furthertestingmaybeneededtoconfirmthe

diagnosis.ThereisachancethatIwillhavethisgeneticconditionbutthatthetestresultsmaybenegative.Duetolimitationsintechnologyand/orincompleteknowledgeofgeneticinteractions,changesinDNAorbiologicalproductsthatcausediseasemaynotbedetectedbythe

test(s).Thetestsofferedareconsideredtobethebestavailableatthistime.Thistestingisoftencomplexandutilizesspecializedmaterials.Howeverthereisalwaysasmallchanceanerrormayoccur.Therealsomaybeapossibilitythatthelaboratoryfindingswillbeuninterpretableorofunknownsignificance.Rarely,findingsmaybesuggestiveofadiseaseorconditiondifferentthantheoriginal

consideration.Theresultsofthetest(s)willbereportedonlythroughaphysicianofrecord,geneticcounselororotheridentifiedhealthcareproviderduetothecomplexityofthetest(s)andtheimplicationsofthetest(s)results.Theresultsareconfidentialtotheextentallowedbylaw.Theresultswillonlybereleasedtoothermedicalprofessionalsorotherpartieswithmywrittenconsentorasotherwiseallowedbylaw.Participationingenetictestingiscompletelyvoluntary.Iunderstandthatmyspecimenwillonlybeusedforthespecificgenetictestingdescribedaboveasauthorizedbymyconsentandthatmysamplewillnotbeusedinanyidentifiablefashionforresearchpurposeswithoutmyconsent.诊断实验室报告的组成成分：检测的结果结果的解释，临床含义结论的依据下一步的建议检测方法介绍，局限性阐明相关信息资源的介绍针对医生的遗传咨询遗传咨询师需要具备的素质遗传学临床遗传学医学遗传学实验室基因诊断的方法法律法规伦理道德心理学An

yu遗传咨询中的人际沟通能力TeachingInformedDecision-makingCounseling美国的遗传咨询师培训（框架）Training

program

(accreditation)（培训班的认证资格）Genetic

counselor

(Certification)

（咨询师的资质）Practice

(continue

education)

（继续教育）An

yu遗传咨询的过程获取信息建立和证实诊断风险评估正确解读信息病人教育，心理咨询病史，临床症状，系谱描述，家族史，以往妊♘情况并发症，致畸因素确定遗传方式美国有资质的培训班(硕士学位)An

yu美国遗传咨询师的培训需要攻读一个两年到两年半的由ABGC认证的遗传咨询硕士学位

（录取同时有生物，遗传学，心理学背景或工作经验的学生）800

小时临床实习50

core

cases

（病例）

in

prenatal

diagnosis,cancerand

pediatrics毕业后需通过American

Board

of

GeneticCounseling（ABGC）

的认证考试成为注册遗传咨询师An

yuBostonUniversitySchoolofMedicineMasters

in

Genetic

Counseling

Training

ProgramThefirstyearofstudyfocusesprimarilyoncourseworkingeneralgenetics

andcounselingskills.Clinical,laboratory,research,andadvocacy

experiencescomplementthedidacticcurriculum.Inaddition,studentsselectaCapstoneProjecttopicandbegintheirresearchduringthesecondsemester.Semester

1GMSGC601–ProfessionalIssuesinGeneticCounseling(3credits)GMSGC603–Embryology,Teratology,andPrenatalGenetics(3credits)GMSGC605–ClinicalApplicationsinHumanGenetics(4

credits)GMSMH703–CounselingTechniquesandHelpingRelationships(3

credits)GMSGC700–GeneticCounselingFieldworkI(2

credits)Semester

2GMSGC600–GeneticDiagnosisandLaboratoryMethods(3

credits)GMSGC601–ProfessionalIssuesinGeneticCounseling,

cont.GMSGC602–ClinicalGenetics(3

credits)GMSGC716–Social,Cultural,andEthicalIssuesinGenetics(3

credits)SummerGMSGC702S–GeneticCounselingFieldworkII(2

credits)BostonUniversitySchoolofMedicineMasters

in

Genetic

Counseling

Training

ProgramThesecondyearofstudyfocusesonclinicalexperienceand

researchprojectdevelopment.

Inaddition,thecourseworkcoversmoreadvancedtopicsinmedicalgenetics,professionalissues,andgeneticcounseling

sub-specialties.Semester

3GMSGC604–CancerGeneticCounseling(3credits)GMSGC703–GeneticCounselingFieldworkIII(2credits)GMSGC711–AdvancedGeneticCounseling(4

credits)GMSMH708–HumanGrowth&Development(3

credits)Semester

4GMSGC704–GeneticCounselingFieldworkIV(2

credits)GMSGC711–AdvancedGeneticCounseling,

cont.GMSGC712–MetabolicGenetics/AdvancedRiskAssessment(3credits)*GMSGC714–AdvancedTopicsinMedicalGenetics(3

credits)An

yuFieldwork

临床实习Theclinicalandnon-clinicalfieldworkexperienceprovidestudentswithopportunitiestodeveloptheircounselingskillsinabroadrangeofsettings.Thesefirst-handexperiencesfamiliarizestudentswithindividualsandfamiliesaffectedbyavarietyofgenetic

disorders.

Thefollowinglistincludessomeofthesettingsavailableforstudentfieldworkexperience:BostonUniversity/BostonMedicalCenter(PrenatalGenetics,PediatricGenetics,CancerGenetics,BreastHealthProgram,HuntingtonDiseaseCenter,AutismResearchCenterofExcellence,DevelopmentalandBehavioralPediatricsclinics,MaternalFetalMedicineclinic,AmyloidTreatmentProgram,

andSickleCellClinic),BostonChildren’sHospital(MetabolismClinic,NeurogeneticsClinic,PrograminGenomics,ComprehensiveBrain

MalformationsProgram,CongenitalMyopathiesClinic,LENDProgram,andDepartmentofOtolaryngology(ENT)andCommunicationEnhancement),MassachusettsGeneralHospital(DevelopmentalNeurogeneticsclinic,Mitochondrialdisordersclinic,Downsyndromeclinic,CancerGenetics,andPrenatalGenetics),Brigham&Women’sHospital(GreenLab:ResearchPrograminTranslationalGenomicsandHealthOutcomes,AdultGenetics,andPrenatalGenetics),TuftsMedicalCenter(GeneralGeneticsandPrenatalGenetics),BethIsraelDeaconessMedicalCenter(PrenatalGeneticsandCancerGenetics),NewtonWellesleyHospital(PrenatalGeneticsandCancerGenetics),PartnersCenterforPersonalizedGeneticMedicineLaboratoryforMolecularMedicine,DanaFarberCancerInstitute,BaystateMedicalCenter,UMassMemorialMedicalCenter,LaheyClinic,RhodeIslandHospital,Women&InfantsHospital,DartmouthHitchcockMedicalCenter,andSouthShore

Hospital.An

yu从医生的角度了解家史TheAmericanAcademyofFamilyPhysicianshasdeveloped

theSCREENmnemonicforobtainingafamily

history:●SomeConcerns:Doyouhaveany(some)concernsabout

diseasesorconditionsthatseemtoruninyour

family?●Reproduction:Havetherebeenanyproblemswith

pregnancy,infertilityorbirthdefectsinyour

family?●Earlydisease,deathordisability:Haveanymembersofyourfamilybeendiagnosedwithachronicdiseaseatanearlyageorhavemembersofyourfamilydiedatanearly

age?●Ethnicity:Howwouldyoudescribeyourethnicity?Or

whatcountrydidyourancestorscome

from?●Non-geneticconditions:Areyouawareofanynon-medicalconditionsorriskfactors,likesmokingorproblemdrinkingthatarepresentinyour

family?从遗传咨询员的角度了解家史Afamilyhistorytakenbyageneticserviceistypicallytargetedtotheconditionofconcernandgoesback(andforward)atleastthreegenerations:thepatient'sparents,siblingsandchildren;grandparents,grandchildren,auntsanduncles;niecesandnephews,grandchildrenandfirstcousins.Informationtobecollectedincludescurrentage,healthstatus,ageatdeathandcauseofdeath,andmedicaldiagnoseswithrelatedenvironmental

exposures.Whenapatternofdiseaseisnoted,morefocusedquestionsareaskedtoassessforfeaturesofpossiblesyndromesanddirecttheassessment.Medicalrecordreviewoffamilymemberscanconfirmdiagnoseswhenthereisuncertaintyorresolveinaccuraciesiffamilymembersprovidediffering

information.Key

factors

suggest

a

genetic

disorderMultipleaffectedindividualsinmultiplegenerationsfromeither

sideofthe

familyOccurrenceofthediseaseatanearlieragethan

usualClosedegreeofrelatedness(ie,firstdegreeorsecond

degreerelative)ofaffected

relativesPresenceofassociatedconditionsinthefamily(eg,theassociationbetweenbreastandovariancancerorcolorectaland

endometrialcancer)Unusualpresentationsofcommonconditions(eg,bilateraldisease

inbreastcancer,breastcancerin

men)Historyofconsanguinity(diseasescausedbyrarerecessivemutationsaremorecommoninfamilieswithmatingsofrelatedindividuals).Consanguinityisgenerallymorerelevantinthepediatricevaluationsthanforconditionswith

adult-onset.GENESGroupofcongenital

anomaliesExceptional

presentationNeurodevelopmental

delayExtreme

pathologySurprisinglaboratory

valuesThisismostrelevantforpediatric

evaluations中国遗传咨询员的工作内涵思考询问了解并根据咨询者的年龄，性别，种族，家史，健康史，生育史等提供个体化遗传健康咨询在临床评估及诊断的基础上建议合适的基因检测项目，解释说明检测的技术有效性，局限性和临床功效性分析确定遗传模式，评估疾病或症状的发生风险与再发风险为临床医生及病人就基因检测报告提供针对性的诠释及咨询，

包括对下一步的建议解释遗传疾病的发病原因、疾病自然发展史、临床表现与可能的干预及治疗措施，

愈后情况促进客户在充分了解情况的基础上做出有关检测、临床干预、生育以及与家庭成员进行沟通的决策使用心理评估识别病患及家属在情感、社会、教育以及文化等方面的理解及接受问题评测客户和/或家庭对出现疾病或存在疾病发风险的理解及反应程度充分了解并为病人及家属提供有效的医学、教育、经济以及心理等社会资源，包括权威性的信息源（书籍文献网站等），专家库，互助组织等信息，引导病患及家属参与诊断及研究项目，提供知情同意的解释。促进客户在充分了解情况的基础上做出有关检测、临床干预、生育以及与家庭成员进行沟通的决策遗传咨询师的工作岗位思考在遗传专科门诊，

是临床遗传专科医疗小组不可缺少的成员之一，帮助临床遗传专科搜集家史，

病史等，解释实验室检测报告并为医生及病人及时提供咨询第三方基因诊断公司及基于医院研究所的基因诊断实验室，是实验室临床服务小组的不可缺少的成员之一。主要负责跟送检医生的联系咨询，检测结果解释及报告的起草。基因健康管理咨询师在了解基因与疾病的关系检测项目研发中也应起到重要作用独立的遗传咨询，基因健康咨询诊所：为需要服务的人群提供独立的专业的遗传，基因健康咨询。社会其他功能部门，

比如法庭，

专利局，病患利益保护组织，罕见病联合会，新闻工作媒体机构等均可设有专门的岗位有具有资质的基因健康管理咨询师负责专门的服务及咨询。我们需要做的铺垫工作Trainingalargenumberofmedicalgenetics

professionalsClinical

geneticistGenetic

counselorMedicalgenetics

researcherMoleculargenetics

specialistPerforminggeneticcounseling

researchEthics/policies/guidelinesAcceptanceApproaches/methodologyeffectivenessCreateshareddisease

knowledgebaseDatabasesPhenotypesPrevalencePenetrancePathogenicityMutation

spectrumAllelefrequencyinheritancemutationmechanismBooksWebsitesfordifferent

audienceGeneratingnovel

knowledgeNovelgeneticriskfactorsfor

phenotypes/diseases/disordersGenotype-phenotype

correlationsLongitudinalfollow-up/cohort

study总结遗传咨询是一项一项构架临床门诊与实验室，理论与技术，专业医生与人民大众，伦理与法律，科学与常理之间桥梁的重要新兴职业，是现代医学不可缺少的内容之一遗传咨询是一项个体化医学，

是“有时是治愈，常常是帮助，总是去安慰”人文医学的具体体现遗传咨询还没有达到精准医学的理想境地15q11.2

deletion

as

a

counselingexampleAmJMedGenetA.

2013

Nov;161A(11):2846-54.15q11.2

deletion

as

a

counselingexample15q11.2

deletion

as

a

counselingexampleCounselingforthe15q11.2deletionismorechallengingthancounselingforothergeneticconditionswithreducedpenetranceandvariable

expressivity.Themostobviousreasonisthefrequently

observedinheritancefromanunaffected

parent.Itisexactlythisabsenceofanyassociatedphenotypeinthetransmittingparentthatmakes

aclinicianhesitatetoattributethefeaturesoftheproband,eventhoughtheassociationsareproveninlargecohorts.Subsequently,itisevenmore

challengingtopredicttheeffectofthisdeletioninthenextgeneration.Thisisaprimeexampleofhow“experience”rather

thanscientificdatacandeterminethewayinwhichwedealwithnewsituationsinclinical

genetics.AmJMedGenetPartA.

161A:2846–2854.4715q11.2

deletion

as

a

counselingexamplePedigree1.OnepatientpresentingwithmoderatetosevereID,carryingadel15q11.2inheritedfromaphenotypicallynormalparent.WhenapatientpresentswithasevereIDphenotypeandtheriskvariantisinheritedfromaphenotypicallynormalparent,onewouldpresumethatanothermutationwithalargeeffectisatthebasisofthephenotype.First,wereasonthatthedel15q11.2isnotveryrarewithaprevalencebetween0.1%and0.8%inthepopulation(TableI).Onecanthereforeassumethatatleast1in1,000(butprobablymore)individualswithIDwillcarrythisvariantpurelybychance,withoutanycausalassociation.Second,thedel15q11.2isariskfactorforneurodevelopmentaldisorders,withasmalleffect.Thissuggeststhepresenceofadditionalmodifyingfactors.ModeratetosevereIDisgenerallythoughttohaveasingle(genetic)cause,incontrastwithmildorborderlineID,whichmoreoftenhasanoligogenicormultifactorialcause.Obviously,anoligogeniccauseofmoderatetosevereIDremainspossible,butuntestedsofar.Recurrencerisk:Ifwefollowthisreasoning,inthispedigree,the

recurrenceriskismorelikelytodependonanothercausalfactor,ratherthanon

thepresenceofadel15q11.2.Whentheothercausalfactorisidentified,theresidualriskforadevelopmentaldisorderinasiblingwhoinheritsonlythe15q11.2deletionisprobably

low.15q11.2

deletion

as

a

counselingexamplePedigree2.OnepatientpresentingwithmildID,carryingthedel15q11.2inheritedfromaphenotypicallynormal

parent.Incontrasttothepreviouspedigree,theprobandisaffected

withmildID.Onewouldpresumethatthedel15q11.2contributessignificantlytothephenotypeandthatpotentialmodifiers(geneticand/orenvironmental)arepresentinaffectedcarriersandabsentinunaffectedcarriers.Suchamodelof“secondhits”wasproposedbyGirirajanetal.,whodescribedthataquarterofindividualswithdel16p12.1carriedasecondgenomicalteration

[Girirajanetal.,2010;VeltmanandBrunner,2010].Ofinterest,del15q11.2hasalowpenetranceyetahighnumberofsecondhits[Girirajanetal.,2012;Rosenfeldetal.,

2012].Recurrencerisk:Theriskforcarrierrelativestohaveadevelopmentaldisordercausedbythedel15q11.2isprobablyhigher

thanthatinPedigree1.Thisisbecausefromaclinicalperspective,thephenotypecanmorelikelybeattributedtothedeletioninPedigree2ascomparedtoPedigree1.Forthoseindividualsnotinheritingthedel15q11.2,theremightbeanelevatedriskduetotheoccurrenceofoligogenicormultifactorialIDintheir

family.15q11.2

deletion

as

a

counselingexamplePedigree3.SiblingswithmildtomoderateID,

discordantorconcordantforaninheriteddel15q11.2andbothparentswithmild

ID.ThecauseoftheIDinthesefamilies,previouslytermed“familialMR,”isgenerallythoughttobemultifactorial,andmostlyrepresentthelowerendofthenormalintelligencedistribution.Currently,fewgeneticstudieshavebeenperformedthatfocusonthispopulation.Itislikelythatinsomefamilies,asinglegeneticcause(suchasdel22q11.2)mayexistwhereasinanunknownproportionof

cases,anoligogeniccausemaybepresent,withforinstancethe

del15q11.2asoneofthe

factors.Recurrencerisk:Insuchfamilies,theempiricrecurrenceriskisprobablyhigh,evenforthosesiblingswhodonotinheritthedel15q11.2.Thereforeweanticipatetheobservationoffamilieswith“multifactorial”IDwhereaffectedsibsarediscordantfor