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

Cell. 2025 Oct 7:S0092-8674(25)01080-3. doi: 10.1016/j.cell.2025.09.012. Online ahead of print.

• PMID: 41061703
• DOI: 10.1016/j.cell.2025.09.012

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.