ReviewDeregulatedRegulators:Disease-CausingcisVariantsinTranscriptionFactorGenesRobinvanderLee,1,2SolenneCorreard,1,2andWyethW.Wasserman1,*Whole-genomesequencingisacceleratingidentificationofnoncodingvariantsthatdisruptgeneexpression,althoughreportsofsuchregulatoryvariantsimpli-catedindiseaseremainrare.Anotablesubsetofdescribedvariantsaffecttran-scriptionfactor(TF)genesandothermasterregulatorsincisthroughdosageeffects.Fromtheliterature,wecompiled46regulatoryvariantslinkedto40TFgenesimplicatedinrarediseases.Wediscussthegenomicgeographyofthesevariantsandtheevidencepresentedfortheirpotentialpathogenicity.Tohelpadvanceresearchoncandidatediseasevariantsintotheliterature,weintroduceanevidenceframeworkspecifictoregulatoryvariants,whichareunder-representedincurrentvariantclassificationguidelines.Theclinicalresearchinterpretationofpatientgenomesmaybeadvancedbyconsideringregulatoryvariants,particularlythosethatderegulateTFgenes.RiseofRegulatoryVariantsinDiseaseWhole-genomesequencing(WGS)isacceleratingtheidentificationofrareandcommongeneticvariationcontributingtohumandiseasesandtraits[1–3].Indeed,clinicalimplementationofWGSoverwhole-exomesequencing(WES)hasthepotentialtocloseadiagnosisgap,asWGSallowsfortheidentificationofstructuralandsmallvariantslocatedoutsidecodingregions[4,5].Asubsetofthesenoncodingvariantsperformaroleinregulatinggeneexpression.TheincorporationofRNA-seqintogenomeinterpretationimprovestheidentificationofdisease-causingvariantsinN7%ofundiagnosedpatients,primarilybyrevealingalteredsplicingthatimpactstheencodingofproteinsbutinsomecasesthroughdetectionofoutlierexpressionlevelsorallele-specificexpressioneffects[6,7].Despiteadvances,itremainschallengingtoestablishcausalitybetweennoncodingvariantsanddiseasephenotypes.Thefocusofthisreviewisoncis-actingvariantsthatimpacttranscriptioninitiationattheDNAlevel,therebyleadingtoalteredlevelsorspatiotemporalpatternsofexpression.Thismayoccurthroughchangestotranscriptionfactor(TF)bindingsites,chromatinlandscapes,and/or3Dge...
