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ARTICLEConsensusStatement:ChromosomalMicroarrayIsaFirst-TierClinicalDiagnosticTestforIndividualswithDevelopmentalDisabilitiesorCongenitalAnomaliesDavidT.Miller,1,*MargaretP.Adam,2,3SwaroopAradhya,4LeslieG.Biesecker,5ArthurR.Brothman,6NigelP.Carter,7DeannaM.Church,8JohnA.Crolla,9EvanE.Eichler,10CharlesJ.Epstein,11W.AndrewFaucett,2LarsFeuk,12JanM.Friedman,13AdaHamosh,14LairdJackson,15ErinB.Kaminsky,2KlaasKok,16IanD.Krantz,17RobertM.Kuhn,18CharlesLee,19JamesM.Ostell,8CarlaRosenberg,20StephenW.Scherer,21NancyB.Spinner,17DimitriJ.Stavropoulos,22JamesH.Tepperberg,23ErikC.Thorland,24JorisR.Vermeesch,25DarrelJ.Waggoner,26MichaelS.Watson,27ChristaLeseMartin,2andDavidH.Ledbetter2,*Chromosomalmicroarray(CMA)isincreasinglyutilizedforgenetictestingofindividualswithunexplaineddevelopmentaldelay/intel-lectualdisability(DD/ID),autismspectrumdisorders(ASD),ormultiplecongenitalanomalies(MCA).PerformingCMAandG-bandedkaryotypingoneverypatientsubstantiallyincreasesthetotalcostofgenetictesting.TheInternationalStandardCytogenomicArray(ISCA)Consortiumheldtwointernationalworkshopsandconductedaliteraturereviewof33studies,including21,698patientstestedbyCMA.Weprovideanevidence-basedsummaryofclinicalcytogenetictestingcomparingCMAtoG-bandedkaryotypingwithrespecttotechnicaladvantagesandlimitations,diagnosticyieldforvarioustypesofchromosomalaberrations,andissuesthataffecttestinter-pretation.CMAoffersamuchhigherdiagnosticyield(15%–20%)forgenetictestingofindividualswithunexplainedDD/ID,ASD,orMCAthanaG-bandedkaryotype(~3%,excludingDownsyndromeandotherrecognizablechromosomalsyndromes),primarilybecauseofitshighersensitivityforsubmicroscopicdeletionsandduplications.Trulybalancedrearrangementsandlow-levelmosaicismaregenerallynotdetectablebyarrays,butthesearerelativelyinfrequentcausesofabnormalphenotypesinthispopulation(1%).AvailableevidencestronglysupportstheuseofCMAinplaceofG-bandedkaryotypingasthefirst-tiercytogeneticdiagnostictestforpatientswithDD/ID,ASD,orMCA.G-bandedkaryotypeanalysisshouldbereservedforpatientswithobviouschromosomalsyndromes(e.g.,Downsyndrome),afamilyhistoryofchromosomalrearrangement,orahistoryofmultiplemiscarriages.IntroductionScopeandPurposeClinicalgenetictesting,includingchromosomeanalysis,isastandardpracticeforpatientswithdiagnosesincludingunexplaineddevelopmentaldelay/intellectualdisability(DD/ID),autismspectrumdisorders(ASD),andmultiplecongenitalanomalies(MCA).Thesecategoriesofdisordersaccountforthelargestproportionofcytogenetictestingbecauseoftheirhighprevalenceinthepopulation.TheincidenceofDD/IDinthegeneralpopulationapproaches3%,1andASDaffects~1:150individuals.2,3Mostpatientslacksufficientspecifichistoryorfeaturesfromphysicalexaminationtosuggestaspecificgenetic(ornon-genetic)cause.Publishedguidelinesfortestingsuchpatientshaveemphasized(1)testingforchromosomalabnormalitiesbyG-bandedkaryotypingand(2)testingforcommonsingle-genedisorders,suchasfragileXsyndrome.4Microarray-basedgenomiccopy-numberanalysisisnowacommonlyorderedclinicalgenetictestforthispatientpopulationandisofferedundervariousnames,suchas‘‘chromosomalmicroarray’’(CMA)and‘‘molecular1DivisionofGeneticsandDepartmentofLaboratoryMedicine,Children’sHospitalBostonandHarvardMedicalSchool,Boston,MA,USA;2DepartmentofHumanGenetics,EmoryUniversitySchoolofMedicine,Atlanta,GA,USA;3DepartmentofPediatrics,UniversityofWashingtonSchoolofMedicine,Seat-tle,WA,USA;4GeneDx,Gaithersburg,MD,USA;5NationalHumanGenomeResearchInstitute,NationalInstitutesofHealth,Bethesda,MD,USA;6Depart-mentofPediatrics,HumanGenetics,PathologyandARUPLaboratories,UniversityofUtahSchoolofMedicine,SaltLakeCity,UT,USA;7WellcomeTrustSangerInstitute,Cambridge,UK,USA;8NationalCenterforBiotechnologyInformation,Bethesda,MD,USA;9NationalGeneticsReferenceLaboratory(Wessex),SalisburyUK;10DepartmentofGenomeSciencesandHowardHughesMedicalInstitute,UniversityofWashingtonSchoolofMedicine,Seattle,WA,USA;11InstituteforHumanGeneticsandDepartmentofPediatrics,UniversityofCalifornia,SanFrancisco,SanFrancisco,CA,USA;12RudbeckLabo-ratory,UppsalaUniversity,Uppsala,Sweden;13DepartmentofMedicalGenetics,UniversityofBritishColumbia,andChild&FamilyResearchInstitute,Vancouver,BritishColumbia,Canada;14DepartmentofPediatricsandMcKusick-NathansInstituteofGeneticMedicine,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,USA;15DepartmentofObstetricsandGynecology,DrexelUniversityCollegeofMedicineandChildren’sHospitalofPhiladel-phia,Philadelphia,PA,USA;16DepartmentofGenetics,UniversityMedicalCentreGroningen,UniversityofGroningen,TheNetherlands;17DepartmentofPediatrics/HumanGenetics,TheChildren’sHospitalofPhiladelphia,UniversityofPennsylvaniaSchoolofMedicine,Philadelphia,PA,USA;18CenterforBiomolecularScienceandEngineering,UniversityofCalifornia,SantaCruz,SantaCruz,CA,USA;19DepartmentofPathology,BrighamandWomen’sHospital,HarvardMedicalSchool,Boston,MA,USA;20DepartmentofGeneticsandEvolutionaryBiology,UniversitySaoPaulo,Brazil;21TheCentreforAppliedGenomicsandPrograminGeneticsandGeneticBiology,TheHospitalforSickChildrenandDepartmentofMolecularGene