Genetic modifiers and ascertainment drive variable expressivity of complex disorders: group Reymond
Matthew Jensen 1 , Corrine Smolen 1 , Anastasia Tyryshkina 1 , Lucilla Pizzo 1 , Jiawan Sun 1 , Serena Noss 1 , Deepro Banerjee 1 , Matthew Oetjens 2 , Hermela Shimelis 2 , Cora M Taylor 2 , Vijay Kumar Pounraja 1 , Hyebin Song 3 , Laura Rohan 1 , Emily Huber 1 , Laila El Khattabi 4 , Ingrid van de Laar 5 , Rafik Tadros 5 , Connie R Bezzina 6 , Marjon van Slegtenhorst 5 , Janneke Kammeraad 5 , Paolo Prontera 7 , Jean-Hubert Caberg 8 , Harry Fraser 9 , Siddharth Banka 10 , Anke Van Dijck 11 , Charles Schwartz 12 , Els Voorhoeve 13 , Patrick Callier 14 , Anne-Laure Mosca-Boidron 14 , Nathalie Marle 14 , Mathilde Lefebvre 14 , Kate Pope 15 , Penny Snell 15 , Amber Boys 15 , Paul J Lockhart 16 , Myla Ashfaq 17 , Elizabeth McCready 18 , Margaret Nowacyzk 18 , Lucia Castiglia 19 , Ornella Galesi 19 , Emanuela Avola 19 , Teresa Mattina 20 , Marco Fichera 21 , Maria Grazia Bruccheri 19 , Giuseppa Maria Luana Mandarà 22 , Francesca Mari 23 , Flavia Privitera 23 , Ilaria Longo 23 , Aurora Curró 23 , Alessandra Renieri 23 , Boris Keren 24 , Perrine Charles 24 , Silvestre Cuinat 25 , Mathilde Nizon 25 , Olivier Pichon 25 , Claire Bénéteau 25 , Radka Stoeva 26 , Dominique Martin-Coignard 26 , Sophia Blesson 27 , Cedric Le Caignec 28 , Sandra Mercier 25 , Marie Vincent 25 , Christa L Martin 2 , Katrin Mannik 29 , Alexandre Reymond 30 , Laurence Faivre 31 , Erik Sistermans 13 , R Frank Kooy 11 , David J Amor 16 , Corrado Romano 21 , Joris Andrieux 32 , Santhosh Girirajan 33
Affiliations
- PMID: 41061703
- DOI: 10.1016/j.cell.2025.09.012
Free article
Abstract
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.
Keywords: ascertainment; autism spectrum disorder; complex disease; copy-number variants; modifiers; multi-hit model; neurodevelopmental; rare variants; variable expressivity.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests The authors declare no competing interests.
Update of
- Genetic modifiers and ascertainment drive variable expressivity of complex disorders. Jensen M, Smolen C, Tyryshkina A, Pizzo L, Banerjee D, Oetjens M, Shimelis H, Taylor CM, Pounraja VK, Song H, Rohan L, Huber E, El Khattabi L, van de Laar I, Tadros R, Bezzina C, van Slegtenhorst M, Kammeraad J, Prontera P, Caberg JH, Fraser H, Banka S, Van Dijck A, Schwartz C, Voorhoeve E, Callier P, Mosca-Boidron AL, Marle N, Lefebvre M, Pope K, Snell P, Boys A, Lockhart PJ, Ashfaq M, McCready E, Nowacyzk M, Castiglia L, Galesi O, Avola E, Mattina T, Fichera M, Bruccheri MG, Mandarà GML, Mari F, Privitera F, Longo I, Curró A, Renieri A, Keren B, Charles P, Cuinat S, Nizon M, Pichon O, Bénéteau C, Stoeva R, Martin-Coignard D, Blesson S, Le Caignec C, Mercier S, Vincent M, Martin C, Mannik K, Reymond A, Faivre L, Sistermans E, Kooy RF, Amor DJ, Romano C, Andrieux J, Girirajan S.medRxiv [Preprint]. 2024 Aug 28:2024.08.27.24312158. doi: 10.1101/2024.08.27.24312158. Update in: Cell. 2025 Oct 7:S0092-8674(25)01080-3. doi: 10.1016/j.cell.2025.09.012. PMID: 39252907Free PMC article.Preprint.
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