Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

Carvill, Gemma L; Heavin, Sinéad B; Yendle, Simone C; McMahon, Jacinta M; O'Roak, Brian J; Cook, Joseph; Khan, Adiba; Dorschner, Michael O; Weaver, Molly; Calvert, Sophie; Malone, Stephen; Wallace, Geoffrey; Stanley, Thorsten; Bye, Ann M E; Bleasel, Andrew; Howell, Katherine B; Kivity, Sara; Mackay, Mark T; Rodriguez-Casero, Victoria; Webster, Richard; Korczyn, Amos; Afawi, Zaid; Zelnick, Nathanel; Lerman-Sagie, Tally; Lev, Dorit; Møller, Rikke S; Gill, Deepak; Andrade, Danielle M; Freeman, Jeremy L; Sadleir, Lynette G; Shendure, Jay; Berkovic, Samuel F; Scheffer, Ingrid E; Mefford, Heather C

doi:10.1038/ng.2646

Cited by 687Epilepsy research and treatmentGenomics and Rare DiseasesGenetics and Neurodevelopmental Disorders

Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

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Carvill, Gemma L, Heavin, Sinéad B, Yendle, Simone C, McMahon, Jacinta M, O'Roak, Brian J, Cook, Joseph, Khan, Adiba, Dorschner, Michael O +26 more·2013·Nature Genetics

DOI 10.1038/ng.2646PMC PMC3704157

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Abstract

Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.

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Pathogenic variants in SYNGAP1 cause a generalised DEE with myoclonic-atonic seizures, absence with eyelid myoclonia, eating-induced reflex seizures and photosensitivity.
“Pathogenic variants in SYNGAP1 cause a generalised DEE with myoclonic-atonic seizures, absence with eyelid myoclonia, eating-induced reflex seizures and photosensitivity [108][109][110] .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [108]
The Introductory section reports five truncating SYNGAP1 variants in patients with epileptic encephalopathy and multiple seizure types. It does not specify myoclonic-atonic seizures, absence with eyelid myoclonia, eating-induced reflex seizures, or photosensitivity for those patients; its photosensitivity finding concerns CHD2. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
CHD2 de novo variants have been identified in individuals with ASD.
“One of the INH-M13 hub genes is CHD2, whose de novo variants have been identified in individuals with ASD.42,43”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [42]
CHD2 is one of the INH-M13 hub genes.
“One of the INH-M13 hub genes is CHD2, whose de novo variants have been identified in individuals with ASD.42,43”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [42]
De novo SNVs in CHD2 have been reported in an ASD subject and in several individuals with a broad spectrum of neurodevelopmental disorders, including ID and epileptic encephalopathy.
“De novo SNVs in CHD2 have been reported in an ASD subject and in several individuals with a broad spectrum of neurodevelopmental disorders, including ID and epileptic encephalopathy8,49,50 (Figure S6).”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [49]

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Authors: Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., Malone, S., Wallace, G., Stanley, T., Bye, A. M. E., Bleasel, A., Howell, K. B., Kivity, S., Mackay, M. T., Rodriguez-Casero, V., Webster, R., Korczyn, A., Afawi, Z., Zelnick, N., Lerman-Sagie, T., Lev, D., Møller, R. S., Gill, D., Andrade, D. M., Freeman, J. L., Sadleir, L. G., Shendure, J., Berkovic, S. F., Scheffer, I. E., & Mefford, H. C.
Affiliations: University of Washington (US)
The University of Melbourne (AU)
Mater Children's Hospital (AU)
University of Otago (NZ)
UNSW Sydney (AU)
The University of Sydney (AU)
Royal Children's Hospital (AU)
Schneider Children's Medical Center (IL)
Children's Hospital at Westmead (AU)
Tel Aviv University (IL)
Wolfson Medical Center (IL)
The Danish Epilepsy Association (DK)
University of Toronto (CA)
Corresponding author: Scheffer, Ingrid E
Mefford, Heather C
ORCID: Carvill, Gemma L
Yendle, Simone C
McMahon, Jacinta M
Calvert, Sophie
Malone, Stephen
Stanley, Thorsten
Bleasel, Andrew
Howell, Katherine B
Kivity, Sara
Mackay, Mark T
Webster, Richard
Korczyn, Amos
Afawi, Zaid
Lev, Dorit
Møller, Rikke S
Gill, Deepak
Andrade, Danielle M
Freeman, Jeremy L
Sadleir, Lynette G
Shendure, Jay
Berkovic, Samuel F
Scheffer, Ingrid E
Mefford, Heather C
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2013-05-26
Volume: 45
Issue: 7
Pages: 825-830
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng.2646
PMC: PMC3704157
OpenAlex: W1963557285
Cited by: 687
References: 41
Citations by year: 2026: 25 · 2025: 28 · 2024: 41 · 2023: 27 · 2022: 41 · 2021: 44 · 2020: 75 · 2019: 66 · 2018: 59 · 2017: 60 · 2016: 63 · 2015: 72 · 2014: 73 · 2013: 10
FWCI: 51.49
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Minerva Access (University of Melbourne) (submittedVersion)
Funders: National Institute of Neurological Disorders and Stroke (R01NS069605)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: epileptic encephalopathy, de novo mutations, CHD2, SYNGAP1, SCN1A, SCN2A, SCN8A, pathogenic variants, candidate genes, phenotypic spectrum, molecular etiology, genetic diagnosis
MeSH terms: Adolescent, Adult, Child, Child, Preschool, DNA Mutational Analysis, DNA-Binding Proteins, Epilepsy, Female, Humans, Male, Mutation, Cohort Studies, Genetic Predisposition to Disease, ras GTPase-Activating Proteins, Young Adult

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Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

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