美國遺傳咨詢模式及經(jīng)驗

美國遺傳咨詢模式及經(jīng)驗報告提綱遺傳咨詢的發(fā)展和定義遺傳咨詢的操作內(nèi)容，對象和原則遺傳咨詢師的培養(yǎng)及需具備的素質(zhì)美國遺傳咨詢師的狀況及資源從美國遺傳咨詢病例看遺傳咨詢的復雜性討論如何開展中國的遺傳咨詢服務遺傳咨詢因需而生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.遺傳咨詢因需而生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遺傳咨詢因需而生遺傳咨詢在美國的早期發(fā)展美國五十年代有了遺傳咨詢概念，在六十年代就呼吁培養(yǎng)專門的遺傳咨詢師。七十年代初開始培訓班并隨后成立了專門的委員會。七十年代末成立了全國范圍的美國遺傳咨詢師學會（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對遺傳咨詢的界定遺傳咨詢是一個幫助人們理解和適應遺傳因素對疾病的作用及其對醫(yī)學、心理和家庭影響的溝通過程。包括通過家族史，

病史來評估疾病在家庭成員中的發(fā)生及其再發(fā)風險；提供有關疾病的遺傳模式、實驗室檢測、治療處理及預防的教育，并提供與疾病相關的各種可以求助的渠道及參與研究的可能性；輔導促進知情選擇和對所患疾病及其再發(fā)風險的逐步認知和接受。遺傳咨詢師的定義FirstGeneticCounselorDefinition

2001“Geneticcounselingisadynamic

psycho-educationalprocesscenteredongenetic

information”Goaltofacilitateclient’sabilitytousegeneticinformationinapersonallymeaningfulwaythatminimizespsychologicaldistressandincreasespersonal

control遺傳咨詢是以遺傳學信息為核心的一個動態(tài)的心理教育過程遺傳咨詢師的作用就是能夠使用遺傳學知識，以個人靈活的方式減少患者的緊張和增加自我的控制信心。NSGC對遺傳咨詢師的界定遺傳咨詢師是經(jīng)過獨特專業(yè)訓練，具碩士研究生學位，并在醫(yī)學遺傳學和咨詢方面有經(jīng)驗的醫(yī)護人員。遺傳咨詢師是健康管理醫(yī)療小組的成員，提供風險評估，并對有一定風險或已經(jīng)診斷為某種遺傳病的個人和家庭提供教育和支持。遺傳咨詢也提供基因檢測報告解釋，并為患者的利益提供支持和倡導。遺傳咨詢的特殊內(nèi)涵Two-way

interaction

(雙向互動)Process

–takes

time

(需要花時間）Patient

autonomy

in

decision-making

（自愿原則）will

vary

based

on

personal,

family

and

cultural

contextsFamilywideimpactdifferentfromotherkindsofdiseases

（家庭廣泛受影響）Psychotherapeutic

component

（心理治療的成分）Appropriately

trained

individuals（需要培訓良好的人員）With

special

knowledge/skills

not

found

in

othermedical/psychological

interactions遺傳檢測和遺傳咨詢的臨床操作構架臨床醫(yī)生遺傳檢測病人及家屬遺傳咨詢專業(yè)培訓資格認證遺傳咨詢是遺傳檢測不可缺少的一個組成部分遺傳咨詢師在診斷實驗室中的作用檢測項目的設計開發(fā)(充分了解基因與疾病的相關性）變異的數(shù)據(jù)分析及解釋(序列及拷貝數(shù)變異的臨床意義)起草報告與用戶（醫(yī)生）溝通遺傳咨詢師在遺傳門診的作用病人臨床評估家史/家譜圖/遺傳模式評估與臨床醫(yī)生溝通跟臨床醫(yī)生及病人解釋實驗室報告，咨詢建議下一步醫(yī)療處理傳統(tǒng)的遺傳咨詢對象遺傳篩查陽性者高齡孕婦，即孕婦年齡達到或者超過35歲曾懷有遺傳病的胎兒或者生育過有遺傳病的孩子父母之一是遺傳病患者有反復發(fā)生的自發(fā)性流產(chǎn)或不孕不育病史的夫婦；超聲異常父母是遺傳病基因攜帶者；夫婦之一有遺傳病家族史；近親婚配；生長異常外環(huán)境致畸物接觸史；腫瘤和遺傳因素明顯的常見?。贿z傳咨詢對象的擴展Frompatientto

non-patientFromhigh-risktogeneral

riskFromMendeliangeneticconditionstocomplex

disordersFromdiseasesto

traits遺傳咨詢必須遵循的倫理、道德原則和法律自愿的原則平等的原則教育咨詢者原則公開信息的原則非指導性的咨詢原則關注咨詢中的心理、社會和情感影響尺度信任和保護隱私的原則遺傳診斷的倫理、道德問題與遺傳診斷相關的法律問題遺傳倫理委員會An

yu針對病人及家屬的遺傳咨詢我的孩子得了什么病我的孩子是怎么得這個病的這個病是遺傳的嗎？家里其他人的風險是多大，誰需要做檢測？會傳給下一代嗎？如何避免此病再發(fā)？這個病的預后如何，孩子長大了會怎樣？能正常上學嗎？

生活能自理嗎？能生育嗎？Shorten

longevityRequirechronic

hospitalizationRequirecostly

treatmentsAffect

mental

orphysical

development,

including

the

ability

to

engageinnormal,independentdaily

activitiesImpair

reproductive

performance,

including

possible

infertility這個病有治嗎？

有什么治療的辦法？哪里可以找到更多有關的信息和得到幫助。做什么檢測可以確認診斷？檢測的有效性及局限性？檢測所帶來的其他問題？知情同意解釋檢測的過程及期待知情同意的要點明確需要提供的血液或其他生物組織及設計的（很小的）風險明確檢測的具體項目及目的檢測結果預期陰性結果，陽性結果的可能性及含義報告對象，

隱私保密后續(xù)如何參加研究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.診斷實驗室報告的組成成分：檢測的結果結果的解釋，臨床含義結論的依據(jù)下一步的建議檢測方法介紹，局限性闡明相關信息資源的介紹針對醫(yī)生的遺傳咨詢遺傳咨詢師需要具備的素質(zhì)遺傳學臨床遺傳學醫(yī)學遺傳學實驗室基因診斷的方法法律法規(guī)倫理道德心理學An

yu遺傳咨詢中的人際溝通能力TeachingInformedDecision-makingCounseling美國的遺傳咨詢師培訓（框架）Training

program

(accreditation)（培訓班的認證資格）Genetic

counselor

(Certification)

（咨詢師的資質(zhì)）Practice

(continue

education)

（繼續(xù)教育）An

yu遺傳咨詢的過程獲取信息建立和證實診斷風險評估正確解讀信息病人教育，心理咨詢病史，臨床癥狀，系譜描述，家族史，以往妊?情況并發(fā)癥，致畸因素確定遺傳方式美國有資質(zhì)的培訓班(碩士學位)An

yu美國遺傳咨詢師的培訓需要攻讀一個兩年到兩年半的由ABGC認證的遺傳咨詢碩士學位

（錄取同時有生物，遺傳學，心理學背景或工作經(jīng)驗的學生）800

小時臨床實習50

core

cases

（病例）

in

prenatal

diagnosis,cancerand

pediatrics畢業(yè)后需通過American

Board

of

GeneticCounseling（ABGC）

的認證考試成為注冊遺傳咨詢師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

臨床實習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從醫(yī)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?從遺傳咨詢員的角度了解家史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中國遺傳咨詢員的工作內(nèi)涵思考詢問了解并根據(jù)咨詢者的年齡，性別，種族，家史，健康史，生育史等提供個體化遺傳健康咨詢在臨床評估及診斷的基礎上建議合適的基因檢測項目，解釋說明檢測的技術有效性，局限性和臨床功效性分析確定遺傳模式，評估疾病或癥狀的發(fā)生風險與再發(fā)風險為臨床醫(yī)生及病人就基因檢測報告提供針對性的詮釋及咨詢，

包括對下一步的建議解釋遺傳疾病的發(fā)病原因、疾病自然發(fā)展史、臨床表現(xiàn)與可能的干預及治療措施，

愈后情況促進客戶在充分了解情況的基礎上做出有關檢測、臨床干預、生育以及與家庭成員進行溝通的決策使用心理評估識別病患及家屬在情感、社會、教育以及文化等方面的理解及接受問題評測客戶和/或家庭對出現(xiàn)疾病或存在疾病發(fā)風險的理解及反應程度充分了解并為病人及家屬提供有效的醫(yī)學、教育、經(jīng)濟以及心理等社會資源，包括權威性的信息源（書籍文獻網(wǎng)站等），專家?guī)欤ブM織等信息，引導病患及家屬參與診斷及研究項目，提供知情同意的解釋。促進客戶在充分了解情況的基礎上做出有關檢測、臨床干預、生育以及與家庭成員進行溝通的決策遺傳咨詢師的工作崗位思考在遺傳?？崎T診，

是臨床遺傳?？漆t(yī)療小組不可缺少的成員之一，幫助臨床遺傳?？扑鸭沂?，

病史等，解釋實驗室檢測報告并為醫(yī)生及病人及時提供咨詢第三方基因診斷公司及基于醫(yī)院研究所的基因診斷實驗室，是實驗室臨床服務小組的不可缺少的成員之一。主要負責跟送檢醫(yī)生的聯(lián)系咨詢，檢測結果解釋及報告的起草?；蚪】倒芾碜稍儙熢诹私饣蚺c疾病的關系檢測項目研發(fā)中也應起到重要作用獨立的遺傳咨詢，基因健康咨詢診所：為需要服務的人群提供獨立的專業(yè)的遺傳，基因健康咨詢。社會其他功能部門，

比如法庭，

專利局，病患利益保護組織，罕見病聯(lián)合會，新聞工作媒體機構等均可設有專門的崗位有具有資質(zhì)的基因健康管理咨詢師負責專門的服務及咨詢。我們需要做的鋪墊工作Trainingalargenumberofmedicalgenetics

professionalsClinical

geneticistGenetic

counselorMedicalgenetics

researcherMoleculargenetics

specialistPerforminggeneticcounseling

researchEthics/policies/guidelinesAcceptanceApproaches/methodologyeffectivenessCreateshareddisease

knowledgebaseDatabasesPhenotypesPrevalencePenetrancePathogenicityMutation

spectrumAllelefrequencyinheritancemutationmechanismBooksWebsitesfordifferent

audienceGeneratingnovel

knowledgeNovelgeneticriskfactorsfor

phenotypes/diseases/disordersGenotype-phenotype

correlationsLongitudinalfollow-up/cohort

study總結遺傳咨詢是一項一項構架臨床門診與實驗室，理論與技術，專業(yè)醫(yī)生與人民大眾，倫理與法律，科學與常理之間橋梁的重要新興職業(yè)，是現(xiàn)代醫(yī)學不可缺少的內(nèi)容之一遺傳咨詢是一項個體化醫(yī)學，

是“有時是治愈，常常是幫助，總是去安慰”人文醫(yī)學的具體體現(xiàn)遺傳咨詢還沒有達到精準醫(yī)學的理想境地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