genomic sequencing identifies secondary findings in a cohort of … · 3 introduction whole exome...

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GenomicsequencingidentifiessecondaryfindingsinacohortofparentstudyparticipantsShortrunningtitle:SecondaryandIncidentalFindingsfromWES/WGSMichelleL.Thompson,PhD1§,CandiceR.Finnila,PhD1§,KevinM.Bowling,PhD1,KyleB.Brothers,MD,PhD2,MatthewB.Neu,BS1,3,MichelleD.Amaral,PhD1,SusanM.Hiatt,PhD1,KellyM.East,MS,CGC1,DavidE.Gray,MS1,JamesM.J.Lawlor,MS1,WhitleyV.Kelley,MS,CGC1,EdwardJ.Lose,MD3,CarlaA.Rich,MA2,ShirleySimmons,RN3,ShawnE.Levy,PhD1,RichardM.Myers,PhD1,GregoryS.Barsh,MD,PhD1,E.MartinaBebin,MD,MPA3,GregoryM.Cooper,PhD1*1HudsonAlphaInstituteforBiotechnology,Huntsville,AL,USA2UniversityofLouisville,Louisville,KY,USA3UniversityofAlabamaatBirmingham,Birmingham,AL,USA§Theseauthorscontributedequallytothiswork.*CorrespondingAuthor:601GenomeWay,Huntsville,AL35806;256-327-9490;[email protected]

.CC-BY-NC 4.0 International licenseis made available under aThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It. https://doi.org/10.1101/183186doi: bioRxiv preprint

https://doi.org/10.1101/183186

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ABSTRACTPURPOSE:Clinicallyrelevantsecondaryvariantswereidentifiedinparentsenrolledwithachild

withdevelopmentaldelayandintellectualdisability.METHODS:Exome/genomesequencing

andanalysisof789‘unaffected’parentswasperformed.RESULTS:Pathogenic/likelypathogenic

variantswereidentifiedin21geneswithin25individuals(3.2%),with11(1.4%)participants

harboringvariationinagenedefinedasclinicallyactionablebytheACMG.Ofthe25individuals,

fivecarriedavariantconsistentwithapreviousclinicaldiagnosis,thirteenwerenotpreviously

diagnosedbuthadsymptomsorfamilyhistorywithprobableassociationwiththedetected

variant,andsevenreportednosymptomsorfamilyhistoryofdisease.Alimitedcarrierscreen

wasperformedyielding15variantsin48(6.1%)parents.Parentswerealsoanalyzedasmate-

pairstoidentifycasesinwhichbothparentswerecarriersforthesamerecessivedisease;this

ledtoonefindinginATP7B.Fourparticipantshadtwofindings(onecarrierandonenon-carrier

variant).Intotal,71ofthe789enrolledparents(9.0%)receivedsecondaryfindings.

CONCLUSION:Weprovideanoverviewoftheratesandtypesofclinicallyrelevantsecondary

findings,whichmaybeusefulinthedesign,andimplementationofresearchandclinical

sequencingeffortstoidentifysuchfindings.

Keywords:Secondaryfindings;genomicsequencing;diseaserisk;CSER;ACMG


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INTRODUCTIONWholeexomeandgenomesequencing(WES/WGS)haveproventobepowerfultestsfor

identifyingclinicallyrelevantgeneticvariation.Theexistenceofsecondaryandincidental

findingshascatalyzeddebateregardingthetypesoffindingsthatshouldbesoughtby

sequencinglabs,thecircumstancesinwhichcertaintypesofvariantsshouldbereturned,and

thenecessaryextentofpatientconsent,education,andgeneticcounseling.TheAmerican

CollegeofMedicalGeneticsandGenomics(ACMG)releasedrecommendationsaboutthe

interpretationofvariantsingenesconsideredtobeclinicallyactionable,includingthosethat

posehighriskofcancerandheartdisease.TheACMGsuggeststhatthesebesoughtand

providedtopatientsthatconsenttoreceivesuchresults1,2.Recommendationsrelatedtouse

ofspecificgenelistsandapproachesforreturningsecondaryfindingswereintendedtobeused

inclinicalcontexts,althoughitisalsoimportanttoexaminethemintranslationalresearch

contexts.

ThroughastudythatwaspartoftheClinicalSequencingExploratoryResearch(CSER)

Consortium3,weassessedtheutilityofWES/WGStoidentifygeneticcausesofdevelopmental

delay,intellectualdisability(DD/ID),andrelatedcongenitalanomalies.Wehavesequenced

affectedprobandsfrom455families,andhaveidentifiedDD/ID-relatedpathogenic/likely

pathogenic(P/LP)variantsin29%ofcases4.AsourDD/IDstudyincludesproband-parenttrios,

wehavetheabilitytoassesssecondaryfindingsinasizablecohortofadults4.

Weusetheterm‘secondaryfindings’throughoutthemanuscripttodescribevariation

identifiedviaproactivesearching5andreportratesandtypesofsecondaryfindingsincontext


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ofreportedsymptomsorfamilyhistory.Ourexperiencesanddatasuggestthevalueofgenomic

sequencinginaclinicalsettingnotonlyfordiseasepatients,butalsoforthosenotcurrently

exhibitinganovertdiseasephenotype.Wedemonstratetheutilityofdisseminationofsuch

findingsinacohortofparentstudyparticipants,andhighlightthisthroughcasestudyanalyses.


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METHODS

Studyparticipantpopulation

Therewasnopublicrecruitmentforthisstudy.Parentandchildren(n=455families)

participantswereenrolledatNorthAlabamaChildren’sSpecialistsinHuntsville,AL.Consent

wasobtainedforstudyparticipationandpublicationofdatageneratedbythisstudy.Review

boardsatWesternInstitutionalReviewBoard(20130675)andtheUniversityofAlabamaat

Birmingham(X130201001)approvedandmonitoredthisstudy.

Patientpreferencesandconsent

WedevelopedthePreferencesInstrumentforGenomicSecondaryResults(PIGSR)6toelicit

parents’preferencesforreceivingcategoriesofsecondaryresults.Thisinstrumentdivides

secondaryfindingsinto13distinctdiseasecategories(Figure1).Resultswerereturnedto

parentparticipantsonlywhentheyoptedtoreceivesecondaryfindings.Decisionsregard

disclosureofsecondaryfindingssolelyintheprobandwerebasedonacombinationofparent

preferencesforthemselvesandmedicalrelevancetotheprobandduringchildhood.Inthecase

ofadoptedprobands,preferencesweresolicitedfromtheadoptiveparentsonbehalfofthe

proband.

Phenotyping

Atenrollment,ageneticcounselorgeneratedathree-generationpedigreebasedonfamily

historyreportedbytheparents/guardiansoftheproband.Parents’healthrecordswerenot

availabletothestudynorwasaphysicalexamperformed.Thegeneticcounselorasked


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questionsrelatedtofamilyhistoryofcancerandsudden/unusualdeathsofadults(e.g.cardiac

arrestoraneurysm).Cascadesequencingwasnotconductedaspartofthisstudy.Wehave(1)

retainedthelanguageusedbytheparticipantand(2)includedanyreportedfamilyhistorythat

isplausiblyrelatedtothephenotypeofconcern.

Returnofresults

Parentparticipantsthatreceivedsecondaryfindingswerescheduledforprivatedisclosurewith

amedicalgeneticistandgeneticcounselor.Theclinicalsignificanceoffindingswasaddressed

anddocumentsdetailingvariantinformationandrelevantresourceswereprovided.Secondary

findingswerenotbydefaultplacedintheparticipant’smedicalrecordandnoformalreferrals

torelevantspecialistsweremade.Iftheparticipantschosetoshareresultswiththeir

healthcareprovider,formalreferralscouldbecoordinated.

Sequencingandvariantinformation

FurtherdetailsregardingWES/WGS,readalignment,variantcalling,filtering,classification,and

validationcanbefoundinourpreviousreport4andinSupplementalMethods.Briefly,we

identifiedsecondaryvariationinACMGgenes1,2;P/LPvariationinClinVar(notinACMGgenes);

recessivevariationinindividualswhoharboredtwoormoreP/LPvariantsinthesamegene;

variationinOMIMgenesinwhichbothparentsofparentalpairharboredP/LPvariationforthe

samerecessivedisorder;andcarrierstatusinformationinCFTR,HEXA,andHBB.OnlyP/LP

variantswerereturned.


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DatasharingIdentifiedvariantsinparentparticipantshavebeensharedthroughClinVaranddbGaP,with

consent.AdditionalinformationisprovidedinSupplementalMethods.


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RESULTS

Demographicsofstudypopulation

Of455enrolledfamilies,424includedatleastoneparent,andbothparentswereavailablefor

365families.Demographicsforthe789parentparticipantsarereportedinTable1.Thestudy

populationhadameanageof41yearsandincluded422femalesand367males.80.5%self-

reportedtobeofEuropeanancestry(“White”),8.5%asAfrican-American(“Black”),and8.2%as

“OtherorMultiracial”.Over25%hadahighschooldiplomaorless,while34.5%reportedsome

collegeeducation(Table1).

PatientPreferences

Onegoalofourstudywastounderstandpatientpreferencesastheyrelatetoreceiptof

secondaryfindingsacrossvariousdiseasecategories6.85%ofparentsrequestedallsecondary

findings,while1.6%declinedtoreceiveallfindings.Themostfrequentlyrequestedcategory

wasriskforgender-specificcancers(breast,ovarian,testicularandprostate;n=584,96.1%).The

leastfrequentlyrequestedresultwasriskfordevelopingobesity(n=542,89.2%)(Figure1).

Carrierstatusfindings

Weconductedalimitedcarrierscreenforvariantsrelevanttocysticfibrosis(CFTR,MIM:

219700),beta-thalassemia(HBB,MIM:613985),sicklecelldisease(HBB,MIM:603903),and

Tay-Sachsdisease(HEXA,MIM:272800),whichareamongthemostcommonMendelian

diseases(averagecarrierriskis1/40)7-9.WeobservedeightP/LPvariantsinCFTRacross35

individuals(4.4%ofparentcohort),fourHEXAvariantsacrossfiveindividuals(0.6%),andthree


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HBBvariantsacrosseightindividuals(1%)(Table2;TableS2).Additionally,wesearchedfor

casesinwhichparental“matepairs”werebothcarriersforvariantsinageneassociatedwitha

recessivedisorder.Thisanalysisledtoreturnablefindingsforoneofthe365parentalpairs;

bothparentsharboredvariationinATP7BassociatedwithWilsondisease(MIM:277900)(Table

S2).

Secondaryvariationinindividualswithapreviousclinicaldiagnosis

P/LPvariantswerefoundinfiveindividualswithaself-reportedpreviousclinicaldiagnosisbut

inwhomaspecificgeneticcausewasunknown.A35-year-oldfemaleindividualwasfoundto

harboraheterozygousmissensevariantinSLC4A1(spherocytosis,MIM:612653),andhad

familyhistoryofrelateddisease(Table3;TableS1).Weidentifiedthreemissensevariants(two

likelyincis)inSLC22A5ina37-year-oldfemalewithrecessivesystemicprimarycarnitine

deficiency(MIM:212140).Finally,acanonicalsplicedonorsite(D1)variantaffectingPKD2was

identifiedina36-year-oldfemalewithpolycystickidneydisease(MIM:613095).Thisindividual

alsoreportedafamilyhistoryofdisease(Table3;TableS1).

Secondarygeneticvariationaffectingcardiacgeneswasidentifiedintwoindividualswitha

previousclinicaldiagnosisandhadafamilyhistoryofcardiovascularphenotypes.One30-year-

oldfemalereportedtohaveexperiencedcardiomyopathypostpartum,hadapaternalfamily

historyofarrhythmia,andherpaternalunclesufferedtwo“heartattacks”priortoage40.She

wasfoundtoharboraframeshiftvariantinDSG2,ageneassociatedwitharrhythmogenicright

ventriculardysplasiaanddilatedcardiomyopathy(MIM:610193,MIM:612877).AlthoughDSG2


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hasnotpersebeenassociatedwithperipartumcardiomyopathy(PPCM),wefinditprobable

thatthevariantexplainsherdiseasehistory.TheclinicalsymptomsofPPCMaresimilartothat

ofdilatedcardiomyopathy10andothergeneticvariantsassociatedwithdilatedcardiomyopathy

mayrepresentsusceptibilityfactorsforPPCM11.Ina52-year-oldmalewithhypertrophic

cardiomyopathyandarrhythmia,weidentifiedmissensevariationinANK2,ageneassociated

withankyrin-B-relatedcardiacarrhythmiaandlongQTsyndrome(MIM:600919).Itisunknown

whetherthisindividualpresentswithlongQTintervals.Additionally,althoughnotclearly

relatedtoANK2variation,thisindividualalsoreportedhisfatherhadischemicheartdisease.

Finally,sixoftheeightparentscarryingP/LPvariationinHBBreportedhavingsicklecellor

thalassemiatraitattimeofenrollment(Table2;TableS2).

Secondarygeneticvariationinsymptomaticindividualsand/orthosethathavefamilyhistory

ofdisease

Weidentifiedsecondaryvariantsin13individualswithnopreviousdiagnosisorgenetictesting

despitethemanifestationofdiseaseand/orfamilyhistory(Table3;TableS1).Given

informationprovidedattimeofenrollment,sixofthesecases(CLCN1,MFN2,BRCA1,BRCA2,

BARD1,PMS2;Table3)wouldhavemetcriteriatojustifygeneticconsultationandtestingvia

standardclinicalrecommendations12,13.Givenadditionalphenotypicinformationacquiredat

returnofresults,twoadditionalcases(SCN4A,HARS;Table3)wouldhavemetsuchcriteria14,15.

Theseeightcasesaredescribedbelow.


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AheterozygousmissensevariantinCLCN1wasidentifiedina29year-oldfemalewhoreported

legcrampsandrestlesslegsbeginninginchildhood.VariationinCLCN1associateswith

myotoniacongenita(MIM:160800)characterizedbymusclestiffnessandinabilitytorelax

musclesaftervoluntarycontraction,symptomsthatareexacerbatedbycoldertemperatures.

Hermotherwasdiagnosedwithmyotoniacongenitawhenshewas10yearsoldandher

maternalgrandfatherhadamusclebiopsyperformedinhis30sduetopresentationof

symptoms,including“stiffness”thatoccurred“especiallyincold[temperatures]”.Inaseparate

case,aheterozygousmissensevariantinMFN2(Charcot-Marie-Tooth(CMT)Diseasetype

2A2A,MIM:609260)wasidentifiedina35-year-oldfemalewhoreportedbalancedifficulties

andweaknesssincechildhoodthathasprogressedtoseverecramping,myalgia,andnumbness

mostprominentlyinlowerextremities,andisexacerbatedbyexercise.Herfamilyhistoryis

notableforneuromusculardisorder,withsimilarsymptomspresentinherbrother,father,

paternalgrandmother,andpaternalaunt.Thoughaclinicianhasnotformallyevaluatedher,

shereportedthatherbrotherwasdiagnosedwithCMT.

Wealsoidentifiedcancerriskvariantsinanumberofindividualswhoreportfamilyhistoryof

cancer.WeidentifiedaframeshiftvariantinBRCA1(familialbreast/ovariancancer,MIM:

604370)ina40-year-oldmalewhosemotherwasdiagnosedwithbreastcancerinherthirties.

Inanothercase,variationinacanonicalacceptorsplicesiteofBRCA2(familialbreast/ovarian

cancer,MIM:612555)wasidentifiedina38-year-oldfemalewhohadahistoryofbreastcancer

onbothsidesofthefamily-paternalgrandmother(diagnosisatunknownage)andmaternal

grandfather(age60).AframeshiftvariantinBARD1(MIM:114480)wasidentifiedina33-year-


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oldfemalewhosematernalgrandmotherhadbladder,lung,andperitonealcanceraswellasa

great-grandmotherdiagnosedwithbreastcancerinherfifties.Additionally,aframeshiftvariant

inPMS2(hereditarynonpolyposiscolorectalcancer;MIM:614337)wasidentifiedina43-year-

oldmalewithfamilyhistoryofcoloncancer-father(diagnosedinhissixties)andpaternalaunt

(forties).Thisindividualalsohadapaternalauntandgrandmotherwhowerediagnosedwith

breastcancerintheirsixtiesandfifties,respectively.Afterreceiptofthisfinding,thestudy

participantfollowed-upwithacolonoscopy,foundtobenegative.Hereportsthathewill

continueperiodicassessment.

Secondaryvariantswerealsoidentifiedintwosymptomaticindividualswhowerenotaware

thattheirsymptomswereunusualandthusneverhadclinicalorgeneticevaluation(Table3).

Atenrollment,neitherindividualreportedrelevantphenotypestothevariantsidentified.In

onecase,a28-year-oldfemalewasfoundtoharborapathogenicmissensevariantinSCN4A,

implicatedinhyperkalemicperiodicparalysisandparamyotoniacongenita(MIMs:170500;

168300),neuromusculardisorderscharacterizedbyintermittentmuscleweaknessand/or

myotonia.Atresultsreturn,shereportedahistoryofpainfulstiffnessduringexercisethat

beganatapproximatelyagefiveandthatherthroat“locksup”afterdrinkingcoldliquids.

Additionally,shereportedthathereyelids“stick”and“becomeheavy”throughouttheday.She

notedthathermotherdisplayssimilarphenotypes.Thisindividualhasplanstofollow-upwitha

neurologist.Inasecondcase,a41-year-oldmalewasfoundtoharborpathogenicvariationin

HARS,associatedwithCharcot-Marie-Toothdisease(MIM:616625)characterizedbygait

difficultiesandsensoryimpairmentcausedbyperipheralneuropathy.Atreturnofresultsthis


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individualindicatedthathewas“clumsy”,dischargedfrommilitarybootcampduetohis

inabilitytomarchinformation,andoftenwearsoutshoesbecauseoffeetshuffling.

Identificationofgeneticriskfactorsinindividualswhoarecurrentlyasymptomaticandhave

nofamilyhistoryofdisease

WealsoidentifiedP/LPvariantsinindividualsthatarecurrentlyasymptomaticandnofamily

historyofdisease(Table3).Twounrelatedindividuals,a52-year-oldfemaleanda50-year-old

male,werefoundtoharborvariationinSCN5A(LongQTsyndrome,MIM:603830)andDSG2

(dilatedcardiomyopathy,MIM:618277),respectively.A31-year-oldmalestudyparticipantwas

foundtoharboramissensevariantinACTN1,associatedwithableedingdisorder(MIM:

615193).Finally,P/LPcancer-associatedvariantswereidentifiedinfourparticipantswithno

personalorfamilyhistory,includingoneineachofMSH2,BARD1,BRCA2,andRET(Table3;

TableS1).Notably,apathogenicmissensevariant(C609Y)inRET,associatedwithmultiple

endocrineneoplasiatype2A(MEN;MIM:171400),medullarythyroidcarcinoma(MTC;MIM:

155240),and/orHirschsprung'sdisease(MIM:142623),wasidentifiedina52-year-oldmale

participantwhoreportednohistoryofRET-associatedcancer.C609Yhasbeenobservedin

manyMTC-affectedindividualsandhasbeendesignatedaslevelBriskfromtheAmerican

ThyroidAssociation(levelDishighestrisk),withexpectedageofonsetoflessthan30years

16,17.RecommendationsforC609Ycarriersvarybutoftenincludeprophylacticthyroidectomyat

ayoungage18,19.However,morerecentstudiesindicateRETC609Ymayhavelowerpenetrance

orlateronsetofMTCthanpreviouslynoted20,21,whichareconsistentwiththeobservationof

nopersonalorfamilyhistoryofcancerinthisfamily.Interestingly,whileC609Ywasnot


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transmittedtotheenrolled,developmentallydelayedproband,thefamilyreportedthatthey

haveanotherdaughter(notenrolled)whohasHirschsprung’sdiseaseandisthereforelikelyto

haveinheritedC609Y.Thefamilywasreferredforgeneticcounselingtotestforthevariantin

theHirschsprung’s-affecteddaughterandthatboththefatheranddaughterfollowupwith

oncologists.

SecondaryfindingsinDD/ID-affectedchildren

Forthreeenrolledchildren,weidentifiedsecondaryvariationnotinheritedfromaparent.Two

individualswhosebiologicalparentswerenotavailableharboredpathogenicvariationinCFTR

(Phe508del)andBRCA2(Leu579*),respectively.Also,asix-year-oldfemaleharboreda

pathogenicdenovovariantinFBN1(Asn2144Ser).Attimeofanalysis,thisprobanddidnot

exhibitMarfanphenotypes(MIM:154700),withexceptionofcrowdedteethandscoliosis.In

threeadditionalprobands,compoundheterozygousvariationassociatedwithrecessivedisease

wasidentified.TwoP/LPvariants,oneinheritedfromeachparent,inOCA2(oculocutaneous

albinismtypeII,MIM:203200)wereidentifiedinaneleven-year-oldmaleandhissix-year-old

brother;bothpresentedwithalbinism.Inathirdcase,anine-year-oldfemalewithcataracts

wasfoundtoinheritaP/LPvariantfromeachparentinFYCO1,ageneassociatedwithcataract

18(MIM:610019).

DISCUSSION

TheACMGestimatedthatsecondaryfindingsingenesrelevanttoadefinedlistofactionable

phenotypes(e.g.cardiacarrhythmias,cancers)wouldbefoundin~1%ofsequencedindividuals


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1,2.WeobservedvariationinACMGgenesin1.4%ofparentparticipants,consistentwiththat

estimateandthe1%-5.6%reportedbyotherresearchandclinicallaboratories22-25.

Ourstudyassessedcarrierstatusinallparticipantsforonlythreegenes,HBB,HEXA,andCFTR,

leadingtotheidentificationofP/LPvariationin~6.1%ofparentparticipants.Thesegeneswere

selectedbasedontheiranticipatedfrequenciesinthepopulationsampledandourdesireto

balanceyieldwithanalyticalandcostburden.Hadweassessedallgenesknowntoassociate

withrecessivedisease26,theburdenofanalysiswouldhaveincreasedsubstantially27,28.

Further,expandedcarrierscreeninganddiscoveryeffortswouldhaveincreasedSanger

validationcostsandthetimerequiredfromgeneticcounselorsandmedicalgeneticistsfor

returnofresults.Thus,whileourchoiceofgenesastargetsforcarrieranalysiswassemi-

arbitrary,therestrictiontoonlythreegenesimposedminimalanalyticalburdenandledtoa

substantialbutmanageableyield.

Oneadditionalmorecomprehensivecarrierstatusstrategyweusedwastosearchwithinboth

parentsofaparentalpairforP/LPvariantsinthesamegene(expandingbeyondCFTR,HBBand

HEXA).Ofthe365parentalpairsenrolled,recessivediseaserisk(i.e.,25%forfuturechildren)

wasidentifiedinone.Thissmallnumberwaslikelyduetoourrelativelystringentcriteriafor

classifyingvariantsofthistypeaspathogenicorlikelypathogenic,butthesenumbersarelikely

togrowinthefutureasevidenceaccruesonthepathogenicityofvariantsingenescausing

Mendeliandisorders22.Thetreatmentofparentalpairsasunitsofanalysisforcarrierstatusis

aneffectivewaytominimizeanalyticalandcostburdenandyeteffectivelycapturethose


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carrierresultslikelytohavethegreatestpotentialimpact.

Copy-numbervariation(CNV)wasnotexploredinparentsasasourceofsecondaryfindings.

Thisdecisionwasdrivenbytheconsiderablemanualscrutinythatisrequiredtoevaluatethe

technicalqualityofCNVs,thecostsandchallengesofCNVvalidation,andtheabsenceofrobust

CNVpopulationfrequencydata,particularlyforsmallerevents.AnalysesofsecondaryP/LP

CNVsmaybeofinteresttofutureeffortstoincreasetheoverallyieldofmedicallyrelevant

variationwithinsequencingdata.

Patientpreferences

Thequestionofwhetherpatientsandresearchparticipantsneedtobeofferedchoicesabout

receivingsecondaryfindingshasbeendebated,especiallyafterthereleaseofACMG’soriginal

secondaryfindingsrecommendationsin20131.Multiplestudieshavedocumentedthatmost

participantswantmost,andusuallyall,possiblesecondaryfindings.Thistrendisconsistent

betweenstudiesaskingthisquestionasahypothetical29-33ortoinformactualreturnofresults

34-37.Consistentwiththesepreviousstudies,thevastmajority(84.8%)ofparentsparticipating

inourstudychosetoreceiveall13categoriesofpotentialsecondaryresults.However,aminor

butsubstantialfractionofparticipants(15.2%)declinedatleastonecategoryofsecondary

results;1.6%declinedallsuchresults.OneofthesecondaryfindingslistedinTable3wasnot

returnedbecausetheparenthaddeclinedtherelevantcategory.


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Challengesassociatedwithvariantinterpretation

Oneofthemostchallengingtaskswhenanalyzingsecondaryfindingsisinterpretationof

geneticvariation,particularlyforvariantsthathavenotbeenpreviouslydescribedinscientific

literatureorinclinicalgeneticdatabases.Eventhosevariantslabeledaspathogenicinvariant

databasesareoftensupportedbyonlyweakunderlyingevidenceorareevenassociatedwith

strongevidenceforbeingbenign38.Interpretationismadeevenmorechallengingwhenan

individualharborspotentialdisease-associatedvariationbutdoesnotpresentwiththe

associatedphenotypeorhaveafamilyhistoryofdisease.Thatsaid,inthisstudy,ACMG

evidencecodeswereassignedandvariantsthatweredeemedtobeP/LPwereofferedfor

returnregardlessofthepresenceorabsenceofanyparticularphenotypeorfamilyhistory.

Evenforthosewithindicationsofdisease,theparticularphenotypesreported(Table3)arenot

necessarilydirectlyrelatedtothepresenceofthegivenvariant.Imprecisionand

incompletenessofself-reporteddiseasesandfamilyhistoriesandlimitationstoknowledgeof

penetranceandexpressivityforanygivengene,andespeciallyanygivenvariant,canallmake

interpretationmorechallenging.

Utilityofsecondaryfindings

Thesecondarygeneticfindingsthatweidentifiedmaybeofconsiderableutilitytotheparent

participants.Forfiveindividuals,wewereabletoconfirm,andgeneticallyexplain,aprevious

clinicaldiagnosis(Table3).Suchinformationmayproveusefulforfutureclinicalmanagement

andindiscussionswithfamilymembersthatmaycarrythesamevariant.Secondarygenetic

findingswerealsoidentifiedin13individualswhoreportedfamilyhistoryorsymptomsthatare


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likelytoassociatedwiththedetectedvariant.Asdescribedindetailintheresultssection,itis

clearthatgeneticcounselingandtestingcould/shouldhavebeenperformedoneightcases

basedonpresentationofsymptomsand/orfamilyhistory.Additionally,weidentifiedsecondary

geneticvariantsinfourindividualswhohaveanincreasedriskofdiseasewithmodestbutnon-

trivialevidencefordisease(twocasesofKCNQ1;onecaseeachofMYBPC3andDDX41).

Throughparticipationinourstudy,theseindividualsnowhaveabetterunderstandingoftheir

causeorriskofdiseaseandareinpositiontobettermanagethatdiseaseorriskofdisease.

Wealsoidentifiedsecondarygeneticvariationinsevenindividualswhoreportneither

symptomsnorfamilyhistoryofdisease(MSH2,RET,BARD1,BRCA2,ACTN1,SCN5A,DSG2).

Thesestudyparticipantsappeartobeatincreasedriskofdiseaseandithasbeensuggested

thattheytofollow-upwithanappropriatespecialist(Table3)inthehopesthatactionscanbe

takentoscreenfor,prevent,ormitigateunobserveddiseaseintheseindividuals.

Finally,wealsoidentifiedsecondaryvariationinDD/IDaffectedprobandsthatwerenot

identifiedinparents,eitherduetounavailabilityofparents,(n=2)orasaresultofthevariant

arisingdenovo(n=1).Further,threechildrenexhibitedrecessivediseaseunrelatedtoDD/ID

andwerefoundtoharborcompoundheterozygousvariationthatexplainedtheirdisease(i.e.

albinismandcataracts).

Challengesofreturningunexpectedvariantstofamilies

Manyparentsinthisstudyhaveexperiencedadiagnosticodysseyinhopesofidentifyingthe


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causeoftheirchild’sdevelopmentaldisabilities.IndividualswhocarriedP/LPsecondary

variantsthereforerequiredcounselingandrecommendationsforclinicalfollow-upregarding

theirsecondaryfindings,inadditiontoinformationregardingthecareandwell-beingoftheir

affectedchildren.Returninggeneticinformationrelevanttoaneworunexpecteddiseaserisk

maybeparticularlyproblematicwhennoresultsarefoundrelevanttotheprimaryindication

fortesting.Inourstudy,51%ofthesecondaryfindingsidentifiedintheparentswere

transmittedtotheDD/ID-affectedproband,and56%ofthe71parentsthatharboreda

secondaryfindingdidnotreceiveaprimaryresultfortheirenrolledDD/ID-affectedchild.The

lackofaprimaryresultmayincreasetheshockvalueofasecondaryfinding.Aparentmay

expecttheconversationtorevolvearoundtheirchild’shealthbutinsteadspendstime

discussingthemeaningoftheirowndiseaseriskand/oranadditionaldiseaseriskrelevantto

theiralreadyaffectedchild.Thisfacthighlightsthepotentialfinancial,emotional,andclinical

implicationsofsecondaryfindingsthatshouldbeclearlyaddressedintheinformedconsent

discussionpriortosequencingsothatfamiliesareawareofallthepossibleoutcomesofthis

typeoftesting.

Conclusions

Ourstudydescribestheidentificationandreturnofsecondaryvariationtoparentswhowere

subjecttogenomicsequencinginhopesofreceivingageneticdiagnosisforadevelopmentally

delayedchild.Althoughthereturnofsecondarygeneticvariationhasbeendebated39,40,alarge

majorityofparentparticipantsinthisstudyoptedtoreceiveallidentifiedsecondaryfindings,

regardlessofdiseasecategory,suggestingthatparticipantsaregenerallyopentoreceiving


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geneticinformationthatmayberelevanttotheirhealth.Thisstudydemonstratestheutilityof

returningsecondaryvariants,asitmayfacilitatepreventativescreeningforindividualswhoare

geneticallypredisposedtoseriousdiseases.Thisinformationcanalsobeusefultoindividuals

whohavebeenclinicallydiagnosedwithaspecificconditionbutforwhomthecausalgenetic

varianthasbeenunknown.Wehavealsoshownthatsecondarygeneticinformationmaylead

toclinicaldiagnosisinindividualswhohaveexperiencedsymptomsrelatedtoadisordernot

previouslydiagnosed.Someindividualsalsodescribedsignificantfamilyhistorythatwouldhave

justified,butdidnotleadto,geneticevaluationindependentoftheirparticipationinthisstudy.

Finally,ourstudydescribesaframeworkforidentifyingsecondarygeneticvariationinabroad

yetmanageablemanner,includingalimitedbutproductivecarrierscreenononlyafew

commonrecessivediseasesalongwithamorecomprehensivescreenthattreatsparentsas

matepairs.Themethodsandresultsrelatedtosecondaryvariationidentificationmaybeofuse

tootherresearchandclinicallaboratoriesthatareconductinggenomicsequencing.


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Acknowledgements

Funding:ThisworkwassupportedbygrantsfromtheUSNationalHumanGenomeResearch

Institute(NHGRI;UM1HG007301)andtheNationalCancerInstitute(NCI;R01CA197139).

Conflictofinterest.Theauthorsdeclarenoconflictsofinterests.

Wearegratefultothefamilieswhocontributedtothisstudy.WethankthestaffatNorth

AlabamaChildren’sSpecialists(Children’sofAlabamainHuntsville,AL),theHudsonAlpha

SoftwareDevelopmentandInformaticsteam,theGenomicServicesLaboratoryat

HudsonAlpha,andtheHudsonAlphaClinicalServicesLab,LLC.whocontributedtodata

acquisitionandanalysis.


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Figure1.Participantpreferencesforreceiptofsecondarygeneticfindings.Participantpreferenceswereassessedforreturnofgeneticvariationacrossanumberofdifferentdiseasecategories.Anoverwhelminglylargemajority(85%)ofstudyparticipantschosetoreceiveanyidentifiedsecondaryvariant,regardlessofdiseaseassociation(n=789).


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Table1.DemographicsofparentparticipantsenrolledintheHudsonAlphaCSERproject. Total,mean(SD)

(n=789)Males,mean(SD)

(n=367)Females,mean(SD)

(n=422)Age 40.95(9.4) 42.63(9.67) 39.49(8.94)Race* Total(%oftotal) Total(%ofmales) Total(%offemales)

White 635(80.5%) 295(80.4%) 340(80.6%)

BlackorAfrican-American

67(8.5%) 28(7.6%) 39(9.2%)

AmericanIndian/Alaska

Native

7(0.9%) 6(1.6%) 1(0.2%)

Other/Multiracial 65(8.2%) 30(8.2%) 35(8.3%)

NoAnswer 15(1.9%) 8(2.2%) 7(1.7%)

Ethnicity* Total(%oftotal) Total(%ofmales) Total(%offemales)HispanicorLatino 32(4.0%) 16(4.4%) 16(3.8%)

NotHispanicorLatino

750(95.1%) 349(95.1%) 401(95.0%)

NoAnswer 7(0.9%) 2(0.5%) 5(1.2%)

Education* Total(%oftotal) Total(%ofmales) Total(%offemales)LessthanHighSchoolDiploma

79(10.0%) 44(12.0%) 35(8.3%)

HighSchoolDiploma/GED

122(15.4%) 67(18.2%) 55(13.0%)

SomeCollege 272(34.5%) 113(30.8%) 159(37.7%)

Bachelor’sDegree 197(25.0%) 84(22.9%) 113(26.8%)

GraduateDegree 118(15.0%) 58(15.8%) 60(14.2%)

NoAnswer 1(0.1%) 1(0.3%) 0(0.0%)*Self-reported


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Table2.UniquevariantsofcarrierstatusinCFTR,HEXA,andHBBUniqueVariantInfo No.ofindividualsCFTR(MIM:219700) 4.4%oftotalpopulation

F508del 22

G685fs 3

D1152H 2

G551D 2

G542* 2

R117H 2

c.489+1G>T 1

F342Hfs 1

HEXA(MIM:272800) 0.6%oftotalpopulationY427Ifs 2

c.986+3A>G 1

c.459+5G>A 1

c.1073+1G>A 1

HBB(MIM:603903;613985) 1%oftotalpopulation

E7V 6

E27K 1

G40* 1


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Table3.Secondaryfindingsofenrolledparentssegregatedinto“Clinicallydiagnosed”,“Notablefamilyhistoryand/orsymptomatic”,and“Currentlyasymptomaticwithnofamilyhistory”. Age

(Male/Female)

Gene VariantInfo AssociatedPhenotype(MIM) Phenotypesorfamilyhistoryreportedbyparentparticipants*

Clinicallydiagnosed(0.6%totalpopulation)

35-F SLC4A1 V488M Spherocytosis,type4(612653)

Clinicallydiagnosedwithspherocytosis;Twodaughtersandfatherwithspherocytosis

37-F SLC22A5 A142S;T440M,R488H

Carnitinedeficiency,systemicprimary(212140) Clinicallydiagnosedwithcarnitinedeficiency

36-F PKD2 c.1319+1G>A Polycystickidneydisease2(613095)

Clinicallydiagnosedwithpolycystickidneydisease(PKD);mother,brother,2nieces,maternalaunt,uncleandgrandmotherwithPKD

30-F DSG2 V986fs

Cardiomyopathy,dilated,1BB;Arrhythmogenicrightventriculardysplasia10

(612877;610193)

Clinicallydiagnosedwithpostpartumcardiomyopathy;Paternalfamilyhistoryofarrhythmia;paternalunclewithtwo“heartattacks”priortoage40

52-M ANK2 E1458G Cardiacarrhythmia,ankryin-B-related,LongQTsyndrome4

(600919)

Clinicallydiagnosedwithhypertrophiccardiomyopathyandarrhythmia;fatherdiedwithischemicheartdisease

Notablefamilyhistoryand/orsymptomatic(1.6%oftotalpopulation)

29-F CLCN1 F413C Myotoniacongenita,dominant(160800)

Legcrampsandrestlesslegsinchildhood,stilloccasionallyhascramps;Motherdiagnosedwithmyotoniacongenita,10years;Maternalgrandfatherwithamusclebiopsyperformedin30sand“stiffness”especiallyincold,30s

35-F MFN2 W740S Charcot-Marie-Toothdisease,axonal,type2A2A(609260)

Historyofmusclewastinginback,lowerextremities;brotherclinicallydiagnosedwithCMT,30s;multiplefamilymembersaffectedwith“unspecifiedmuscledisorder”

40-M BRCA1 G1756fs Breast-ovariancancer,familial1(604370)

Motherwithbreastcancer,30s

38-F BRCA2 c.8488-1G>A Breast-ovariancancer,familial2(612555)

Maternalgrandfatherwithbilateralbreastcancer,60s;Paternalgrandmotherwithbreastcancer,ageunknown

33-F BARD1 E652fs Breastcancersusceptibility(114480)

Maternalgreat-grandmotherwithbreastcancer,50s;Maternalgrandmotherhadbladder,lung,andperitonealcancer,ageunknown

43-M PMS2 P246fsHereditarynonpolyposiscolorectalcancer,type4

(614337)

Father(60s)andpaternalaunt(40s)hadcoloncancer;Paternalaunt(60s)andgrandmother(50s)withbreastcancer

28-F SCN4A T1313M Paramyotoniacongenita(168300)

Atenrollment,noreportofneuromuscularphenotypes.Atreturnofresults,indicatedthatshehadmusclestiffnessbutalwaysthoughtshewas“easilyfatigued”andhad“lowstamina”;Motherdisplayssimilarsymptoms

41-M HARS R137Q Charcot-Marie-Tooth,axonal,type2W(616625)

Atenrollment,noreportofneuromuscularphenotypes.Atreturnofresults,indicatedthathehadCMT-associatedphenotypes.Alwaysthoughthewas“justclumsy”

32-F KCNQ1 R366W LongQTsyndrome1(192500) Fatherwithcoronaryarterydiseasewithtripleby-pass,early50s,paternalauntwithearly-onsetstroke,late30s


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47-M KCNQ1 P7S LongQTsyndrome1

(192500))

Mother“fainted”and“hitthefloor”-wastoldthisimpactpreventedcardiacarrest

39-M MYBPC3 E542Q

Hypertrophiccardiomyopathy4;Dilatedcardiomyopathy1MM(115197;615396)

“Leakyheartvalve”;Dadhaspacemakerandmomhas“leakyheartvalve”,60s

30-M DDX41 D140fs

Susceptibilitytofamilialmyeloproliferative/lymphoproliferativeneoplasms(616871)

Paternalcousinwithlymphoma“unspecified”,ageunknown

37-F MC4R C271Y Obesity,autosomaldominant(601665) Obese(BMI:41)

Currentlyasymptomaticwithnofamilyhistory(0.9%oftotalpopulation)

52-F SCN5A T1303M LongQTsyndrome-3(603830)

Recommendedtohavecardiovascularevaluation

50-M DSG2 E1020fs

Cardiomyopathy,dilated,1BB;Arrhythmogenicrightventriculardysplasia10

(612877;610193)

Recommendedtohavecardiovascularevaluation

31-M ACTN1 V105I

Bleedingdisorder,platelettype,15(615193)

Recommendedtohaveacompletebloodcountandfunctionalplateletstudy

33-M MSH2 Y570fs

Hereditarynonpolyposiscolorectalcancer,type1

(120435)

Recommendedtofollow-upandhavecolonoscopy

36-F BARD1 Y404* Breastcancersusceptibility(114480)

Recommendedtodiscusswithphysicianandcancergeneticcounselor

47-M BRCA2 V220fs Breast-ovariancancer,familial2(612555)

Recommendedtohaveself-andclinical-breastexams;Discusswithcancergeneticcounselor

52-M RET C609Y

Medullarythyroidcarcinoma(155240);SusceptibilitytoHirschsprungdisease1

(142623)

Recommendedtofollow-upandtestdaughterwithHirschsprung’sdisease

*Wehave(1)retainedthelanguageusedbytheparticipantand(2)includedanyreportedfamilyhistorythatisplausiblyrelatedtothephenotypeofconcern.


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