biostudies-literatureUnknownJensen MSwiss National Science FoundationNational Institute for Health Research (NIHR)NLM NIH HHSNIGMS NIH HHSVariable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants towards clinical outcomes of 2,252 individuals with primary variants. Among 132 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risk for specific developmental features, including short tandem repeats for neurological defects and SNVs for microcephaly, while additional disease-associated variants conferred multiple genetic diagnoses. Within disease and population cohorts of 773 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants towards clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as 16medRxiv : the preprint server for health sciences2024.08.27.24312158https://www.ebi.ac.uk/biostudies/studies/S-EPMC11383473biostudies-literatureGenetic modifiers and ascertainment drive variable expressivity of complex disorders.PMC11383473182632NIHR203308R01 GM121907T32 GM102057T32 LM012415Voorhoeve EKeren BTyryshkina ALe Caignec CMandara GMLAvola EPounraja VKFraser HBlesson SGirirajan SBeneteau CKooy RFBruccheri MGMercier SHuber EMarle NReymond AMari FBezzina CPichon OMannik KPope KRomano CPizzo LPrivitera FFichera MMosca-Boidron ALStoeva RKammeraad JGalesi OLongo ICaberg JHLefebvre MOetjens Mvan de Laar IFaivre LCuinat SRenieri AEl Khattabi LTadros RLockhart PJSistermans ESchwartz CAmor DJJensen MBanerjee DTaylor CMRohan LCallier PBanka SCastiglia LCurro ABoys ACharles PVan Dijck AMartin-Coignard Dvan Slegtenhorst MProntera PSnell PVincent MSong HMartin CShimelis HAshfaq MNizon MSmolen CAndrieux JMcCready ENowacyzk MMattina TfalseGenetic modifiers and ascertainment drive variable expressivity of complex disorders.Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants towards clinical outcomes of 2,252 individuals with primary variants. Among 132 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risk for specific developmental features, including short tandem repeats for neurological defects and SNVs for microcephaly, while additional disease-associated variants conferred multiple genetic diagnoses. Within disease and population cohorts of 773 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants towards clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as 162024-01-01T00:00:00Z2024 Aug2026-06-07T03:25:31.017Z2025-04-07T00:13:47.176ZS-EPMC113834733925290710.1101/2024.08.27.24312158