Royal College of Surgeons in Ireland
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Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

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journal contribution
posted on 2024-02-09, 13:59 authored by Ludovica Montanucci, Gianpiero CavalleriGianpiero Cavalleri, Norman DelantyNorman Delanty, Colin Doherty, Arif Shukralla, Hany El-NaggarHany El-Naggar, Peter Widdess-Walsh, Dennis Lal
Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.


Wellcome Trust [203914/Z/16/Z]

The Hartwell Foundation (Individual Biomedical Research Award)

National Institute for Neurological Disorders and Stroke (K02 NS112600)

Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Intellectual and Developmental Disabilities Research Center (IDDRC) at Children’s Hospital of Philadelphia and the University of Pennsylvania (U54 HD086984)

German Research Foundation (HE5415/3-1, HE5415/5-1, HE5415/6-1, HE5415/7-1)

National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001878)

Institute for Translational Medicine and Therapeutics’ (ITMAT) at the Perelman School of Medicine of the University of Pennsylvania

Children’s Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN)

NHGRI T32HG002295

NSF GRFP #2017240332

National Human Genome Research Institute (NHGRI)

National Heart, Lung, and Blood Institute (NHLBI)

NHGRI grant UM1 HG008895

NHGRI grant 5U01HG009088-02



The original article is available at

Published Citation

Montanucci L. et al. Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals. Nat Commun. 2023;14(1):4392.

Publication Date

20 July 2023

PubMed ID



  • Beaumont Hospital
  • School of Pharmacy and Biomolecular Sciences
  • Physiology and Medical Physics

Research Area

  • Neurological and Psychiatric Disorders


Nature Pub. Group


  • Published Version (Version of Record)