Cell · 2025

Genetic modifiers and ascertainment drive variable expressivity of complex disorders.

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

Аннотация

Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants on the clinical outcomes of 2,455 individuals with primary variants. Among 124 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risks for specific developmental features, including short tandem repeats for neurological defects. Network analysis suggested distinct mechanisms involving 16p12.1 genes and secondary variants specific to each proband. Within disease and population cohorts of 976 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants on clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as the 16p11.2 deletion and CHD8 variants, and 1,528 probands 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 personalized genomic architecture of complex disorders.

Предметные рубрики MeSH

Humans Male Chromosomes, Human, Pair 16 Female DNA-Binding Proteins Phenotype Genetic Predisposition to Disease Genes, Modifier Chromosome Deletion Transcription Factors

Genetic modifiers and ascertainment drive variable expressivity of complex disorders.

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Аннотация

Предметные рубрики MeSH