Genetic modifiers and ascertainment drive variable expressivity of complex disorders-Reference-Cited by-同舟云学术

Genetic modifiers and ascertainment drive variable expressivity of complex disorders

Published:2024-08-28 Issue: Volume: Page:
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Jensen Matthew^ORCID,Smolen Corrine^ORCID,Tyryshkina Anastasia^ORCID,Pizzo Lucilla^ORCID,Banerjee Deepro^ORCID,Oetjens Matthew^ORCID,Shimelis Hermela^ORCID,Taylor Cora M.^ORCID,Pounraja Vijay Kumar^ORCID,Song Hyebin^ORCID,Rohan Laura,Huber Emily^ORCID,El Khattabi Laila^ORCID,van de Laar Ingrid^ORCID,Tadros Rafik^ORCID,Bezzina Connie^ORCID,van Slegtenhorst Marjon,Kammeraad Janneke^ORCID,Prontera Paolo^ORCID,Caberg Jean-Hubert^ORCID,Fraser Harry^ORCID,Banka Siddhartha,Van Dijck Anke^ORCID,Schwartz Charles,Voorhoeve Els^ORCID,Callier Patrick^ORCID,Mosca-Boidron Anne-Laure^ORCID,Marle Nathalie^ORCID,Lefebvre Mathilde^ORCID,Pope Kate^ORCID,Snell Penny^ORCID,Boys Amber^ORCID,Lockhart Paul J.^ORCID,Ashfaq Myla^ORCID,McCready Elizabeth^ORCID,Nowacyzk Margaret,Castiglia Lucia^ORCID,Galesi Ornella^ORCID,Avola Emanuela^ORCID,Mattina Teresa^ORCID,Fichera Marco^ORCID,Bruccheri Maria Grazia,Mandarà Giuseppa Maria Luana^ORCID,Mari Francesca^ORCID,Privitera Flavia^ORCID,Longo Ilaria^ORCID,Curró Aurora^ORCID,Renieri Alessandra^ORCID,Keren Boris^ORCID,Charles Perrine^ORCID,Cuinat Silvestre^ORCID,Nizon Mathilde^ORCID,Pichon Olivier^ORCID,Bénéteau Claire^ORCID,Stoeva Radka^ORCID,Martin-Coignard Dominique,Blesson Sophia,Le Caignec Cedric^ORCID,Mercier Sandra^ORCID,Vincent Marie^ORCID,Martin Christa^ORCID,Mannik Katrin^ORCID,Reymond Alexandre^ORCID,Faivre Laurence^ORCID,Sistermans Erik^ORCID,Kooy R. Frank^ORCID,Amor David J.^ORCID,Romano Corrado^ORCID,Andrieux Joris,Girirajan Santhosh^ORCID

Abstract

SUMMARYVariable 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 16p11.2 deletion andCHD8variants, and 1,084 without primary variants, showed that phenotypic associations differed by primary variant context and were influenced by synergistic interactions between primary and secondary variants. Our study provides a paradigm to dissect the genomic architecture of complex disorders towards personalized treatment.

Publisher

Cold Spring Harbor Laboratory

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