Genetic modifiers and ascertainment drive variable expressivity of complex disorders

Matthew Jensen; Corrine Smolen; Anastasia Tyryshkina; Lucilla Pizzo; 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 Bezzina; Marjon van Slegtenhorst; Janneke Kammeraad; Paolo Prontera; Jean-Hubert Caberg; Harry Fraser; Siddhartha 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 Martin; Katrin Mannik; Alexandre Reymond; Laurence Faivre; Erik Sistermans; R. Frank Kooy; David J. Amor; Corrado Romano; Joris Andrieux; Santhosh Girirajan

doi:10.1101/2024.08.27.24312158

Prépublication

Genetic modifiers and ascertainment drive variable expressivity of complex disorders

Matthew Jensen, Corrine Smolen, Anastasia Tyryshkina, Lucilla Pizzo, Deepro Banerjee, Matthew Oetjens, Hermela Shimelis, Cora M. Taylor, Vijay Kumar Pounraja, Hyebin Song, …

medRxiv

Cold Spring Harbor Laboratory Press, 1.1

28/08/2024

DOI: https://doi.org/10.1101/2024.08.27.24312158

PMID: 39252907

Résumé

Genetic and Genomic Medicine

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.

Indicateurs

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Détails

Titre: Genetic modifiers and ascertainment drive variable expressivity of complex disorders
Créateurs - sans rôle: Matthew Jensen - Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park
Corrine Smolen - Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park
Anastasia Tyryshkina - Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park
Lucilla Pizzo - Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park
Deepro Banerjee - Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park
Matthew Oetjens - Autism & Developmental Medicine Institute
Hermela Shimelis - Autism & Developmental Medicine Institute
Cora M. Taylor - Autism & Developmental Medicine Institute
Vijay Kumar Pounraja - Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park
Hyebin Song - Department of Statistics, Pennsylvania State University, University Park
Laura Rohan - Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park
Emily Huber - Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park
Laila El Khattabi - Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité
Ingrid van de Laar - Department of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam
Rafik Tadros - Department of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam
Connie Bezzina - Department of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam
Marjon van Slegtenhorst - Department of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam
Janneke Kammeraad - Department of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam
Paolo Prontera - Medical Genetics Unit, Hospital Santa Maria della Misericordia
Jean-Hubert Caberg - Centre Hospitalier Universitaire de Liège. Domaine Universitaire du Sart Tilman
Harry Fraser - Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester
Siddhartha Banka - Manchester Centre for Genomic Medicine, St. Mary’s Hospital, Central Manchester University Hospitals, NHS Foundation Trust Manchester Academic Health Sciences Centre
Anke Van Dijck - Department of Medical Genetics, University and University Hospital Antwerp
Charles Schwartz - Greenwood Genetic Center
Els Voorhoeve - Department of Clinical Genetics, Amsterdam UMC
Patrick Callier - Center for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon
Anne-Laure Mosca-Boidron - Center for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon
Nathalie Marle - Center for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon
Mathilde Lefebvre - Laboratoire de Genetique Chromosomique et Moleculaire
Kate Pope - Bruce Lefroy Centre, Murdoch Children’s Research Institute
Penny Snell - Bruce Lefroy Centre, Murdoch Children’s Research Institute
Amber Boys - Bruce Lefroy Centre, Murdoch Children’s Research Institute
Paul J. Lockhart - Department of Paediatrics, University of Melbourne
Myla Ashfaq - Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center
Elizabeth McCready - Department of Pathology and Molecular Medicine, McMaster University
Margaret Nowacyzk - Department of Pathology and Molecular Medicine, McMaster University
Lucia Castiglia - Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS
Ornella Galesi - Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS
Emanuela Avola - Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS
Teresa Mattina - Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS
Marco Fichera - Section of Clinical Biochemistry and Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine
Maria Grazia Bruccheri - Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS
Giuseppa Maria Luana Mandarà - Medical Genetics, ASP Ragusa
Francesca Mari - Laboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute
Flavia Privitera - Laboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute
Ilaria Longo - Laboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute
Aurora Curró - Laboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute
Alessandra Renieri - Laboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute
Boris Keren - Assistance Publique – Hôpitaux de Paris
Perrine Charles - Département de Génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université
Silvestre Cuinat - CHU Nantes, Medical Genetics Department
Mathilde Nizon - CHU Nantes, Medical Genetics Department
Olivier Pichon - CHU Nantes, Medical Genetics Department
Claire Bénéteau - Université de Nantes
Radka Stoeva - Université de Nantes
Dominique Martin-Coignard - Service de Cytogenetique, CHU de Le Mans
Sophia Blesson - Department of Genetics, Bretonneau University Hospital
Cedric Le Caignec - Toulouse Neuro Imaging, Center, Inserm, UPS, Université de Toulouse
Sandra Mercier - Department of Genetics, Bretonneau University Hospital
Marie Vincent - Department of Genetics, Bretonneau University Hospital
Christa Martin - Autism & Developmental Medicine Institute
Katrin Mannik - Health2030 Genome Center, Fondation Campus Biotech
Alexandre Reymond - University of Lausanne
Laurence Faivre - Laboratoire de Genetique Chromosomique et Moleculaire
Erik Sistermans - Department of Clinical Genetics, Amsterdam UMC
R. Frank Kooy - Department of Medical Genetics, University and University Hospital Antwerp
David J. Amor - Department of Clinical Genetics, Amsterdam UMC
Corrado Romano - Section of Clinical Biochemistry and Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine
Joris Andrieux - Institut de Genetique Medicale, Hopital Jeanne de Flandre
Santhosh Girirajan - Department of Anthropology, Pennsylvania State University, University Park
Détails de publication: medRxiv
Éditeur: Cold Spring Harbor Laboratory Press
Édition: 1.1
Nombre de pages: 72
Identifiants: 99158775709311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Preprint