Genetic modifiers and ascertainment drive variable expressivity of complex disorders
Détails
ID Serval
serval:BIB_A51E7DFEFA16
Type
Autre: (aucun autre type ne convient)
Collection
Publications
Institution
Titre
Genetic modifiers and ascertainment drive variable expressivity of complex disorders
Date de publication
28/08/2024
Langue
anglais
Résumé
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 16p11.2 deletion and CHD8 variants, 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.
Pubmed
Création de la notice
25/09/2024 9:04
Dernière modification de la notice
26/09/2024 6:19