
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.27.24312158
preprint
1
Article
Genetic modifiers and ascertainment drive variable expressivity of complex disorders
Jensen Matthew http://orcid.org/0000-0002-5153-8543

Smolen Corrine http://orcid.org/0000-0001-5951-5365

Tyryshkina Anastasia http://orcid.org/0000-0001-8710-5590

Pizzo Lucilla http://orcid.org/0000-0001-9325-7283

Banerjee Deepro http://orcid.org/0000-0003-4877-0920

Oetjens Matthew http://orcid.org/0000-0003-0955-9356

Shimelis Hermela http://orcid.org/0000-0003-1284-8909

Taylor Cora M. http://orcid.org/0000-0002-3813-873X

Pounraja Vijay Kumar http://orcid.org/0000-0002-9710-189X

Song Hyebin http://orcid.org/0000-0003-1875-5009

Rohan Laura
Huber Emily http://orcid.org/0000-0003-0123-7141

El Khattabi Laila http://orcid.org/0000-0003-1546-5276

van de Laar Ingrid http://orcid.org/0000-0002-2523-1230

Tadros Rafik http://orcid.org/0000-0002-1472-0258

Bezzina Connie http://orcid.org/0000-0002-0633-3514

van Slegtenhorst Marjon
Kammeraad Janneke http://orcid.org/0000-0002-1556-9422

Prontera Paolo http://orcid.org/0000-0003-4960-9223

Caberg Jean-Hubert http://orcid.org/0000-0003-4083-3907

Fraser Harry http://orcid.org/0000-0002-2732-5994

Banka Siddhartha
Van Dijck Anke http://orcid.org/0000-0002-6713-2943

Schwartz Charles
Voorhoeve Els http://orcid.org/0000-0002-7426-395X

Callier Patrick http://orcid.org/0000-0002-9794-1848

Mosca-Boidron Anne-Laure http://orcid.org/0000-0002-9130-1495

Marle Nathalie http://orcid.org/0000-0003-0690-0790

Lefebvre Mathilde http://orcid.org/0009-0008-4761-1462

Pope Kate http://orcid.org/0000-0002-6232-3759

Snell Penny http://orcid.org/0000-0002-9821-5282

Boys Amber http://orcid.org/0000-0003-0802-1351

Lockhart Paul J. http://orcid.org/0000-0003-2531-8413

Ashfaq Myla http://orcid.org/0000-0002-0502-5659

McCready Elizabeth http://orcid.org/0000-0002-7952-2279

Nowacyzk Margaret
Castiglia Lucia http://orcid.org/0000-0002-3261-8847

Galesi Ornella http://orcid.org/0000-0002-7877-938X

Avola Emanuela http://orcid.org/0000-0002-6740-665X

Mattina Teresa http://orcid.org/0000-0001-6143-6682

Fichera Marco http://orcid.org/0000-0002-8225-6880

Bruccheri Maria Grazia
Mandarà Giuseppa Maria Luana http://orcid.org/0000-0003-3927-0908

Mari Francesca http://orcid.org/0000-0003-1992-1654

Privitera Flavia http://orcid.org/0000-0002-0316-4903

Longo Ilaria http://orcid.org/0000-0003-2056-8763

Curró Aurora http://orcid.org/0000-0002-7321-9148

Renieri Alessandra http://orcid.org/0000-0002-4882-9083

Keren Boris http://orcid.org/0000-0001-6172-8247

Charles Perrine http://orcid.org/0000-0002-3108-2171

Cuinat Silvestre http://orcid.org/0000-0002-0763-5661

Nizon Mathilde http://orcid.org/0000-0003-2170-4210

Pichon Olivier http://orcid.org/0000-0001-6764-0713

Bénéteau Claire http://orcid.org/0000-0002-1682-523X

Stoeva Radka http://orcid.org/0000-0002-6383-8201

Martin-Coignard Dominique
Blesson Sophia
Le Caignec Cedric http://orcid.org/0000-0002-0598-653X

Mercier Sandra http://orcid.org/0000-0002-6627-8748

Vincent Marie http://orcid.org/0000-0003-1010-5618

Martin Christa http://orcid.org/0000-0002-8071-5780

Mannik Katrin http://orcid.org/0000-0001-7819-4536

Reymond Alexandre http://orcid.org/0000-0003-1030-8327

Faivre Laurence http://orcid.org/0000-0001-9770-444X

Sistermans Erik http://orcid.org/0000-0001-7187-4563

Kooy R. Frank http://orcid.org/0000-0003-2024-0485

Amor David J. http://orcid.org/0000-0001-7191-8511

Romano Corrado http://orcid.org/0000-0003-1049-0683

Andrieux Joris
Girirajan Santhosh http://orcid.org/0000-0003-0598-4945

28 8 2024
2024.08.27.24312158https://creativecommons.org/licenses/by-nd/4.0/ This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
http://medrxiv.org/lookup/doi/10.1101/2024.08.27.24312158
nihpp-2024.08.27.24312158.pdf
SUMMARY

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.
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