| Title: | Genetic modifiers and ascertainment drive variable expressivity of complex disorders |
| Journal: | Cell |
| Published: | 7 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41061703/ |
| DOI: | https://doi.org/10.1016/j.cell.2025.09.012 |
| URL: | https://pure.amsterdamumc.nl/en/publications/4030281c-eaf8-4ea5-a293-e5029ae8f018 |
Publication 19261
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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.</p>
10 Keywords
- Chromosome Deletion
- Chromosomes, Human, Pair 16
- DNA-Binding Proteins
- Female
- Genes, Modifier
- Genetic Predisposition to Disease
- Humans
- Male
- Phenotype
- Transcription Factors
72 Authors
- Matthew Jensen
- Corrine Smolen
- Anastasia Tyryshkina
- Lucilla Pizzo
- Jiawan Sun
- Serena Noss
- Deepro Banerjee
- Matthew Oetjens
- Hermela Shimelis
- Cora M Taylor
- Vijay Kumar Pounraja
- Hyebin Song
- Laura Rohan
- Emily Huber
- Laila El Khattabi
- Ingrid van de Laar
- Rafik Tadros
- Connie R Bezzina
- Marjon van Slegtenhorst
- Janneke Kammeraad
- Paolo Prontera
- Jean-Hubert Caberg
- Harry Fraser
- Siddharth Banka
- Anke Van Dijck
- Charles Schwartz
- Els Voorhoeve
- Patrick Callier
- Anne-Laure Mosca-Boidron
- Nathalie Marle
- Mathilde Lefebvre
- Kate Pope
- Penny Snell
- Amber Boys
- Paul J Lockhart
- Myla Ashfaq
- Elizabeth McCready
- Margaret Nowacyzk
- Lucia Castiglia
- Ornella Galesi
- Emanuela Avola
- Teresa Mattina
- Marco Fichera
- Maria Grazia Bruccheri
- Giuseppa Maria Luana Mandarà
- Francesca Mari
- Flavia Privitera
- Ilaria Longo
- Aurora Curró
- Alessandra Renieri
- Boris Keren
- Perrine Charles
- Silvestre Cuinat
- Mathilde Nizon
- Olivier Pichon
- Claire Bénéteau
- Radka Stoeva
- Dominique Martin-Coignard
- Sophia Blesson
- Cedric Le Caignec
- Sandra Mercier
- Marie Vincent
- Christa L Martin
- Katrin Mannik
- Alexandre Reymond
- Laurence Faivre
- Erik Sistermans
- R Frank Kooy
- David J Amor
- Corrado Romano
- Joris Andrieux
- Santhosh Girirajan
1 Application
| Application ID | Title |
|---|---|
| 45023 | Understanding the genetic complexity of neuropsychiatric features in copy-number variant disorders |
Enabling scientific discoveries that improve human health