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Article: Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

TitleUltra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
Authors
Keywordsepilepsy
seizures
epileptic encephalopathy
exome
sequencing
Issue Date2019
PublisherCell Press. The Journal's web site is located at http://www.cell.com/ajhg/home
Citation
The American Journal of Human Genetics, 2019, v. 105 n. 2, p. 267-282 How to Cite?
AbstractSequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
Persistent Identifierhttp://hdl.handle.net/10722/280110
ISSN
2023 Impact Factor: 8.1
2023 SCImago Journal Rankings: 4.516
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorBaum, LW-
dc.contributor.authorSham, PC-
dc.contributor.authorEpi25 Collaborative,-
dc.date.accessioned2020-01-06T02:01:07Z-
dc.date.available2020-01-06T02:01:07Z-
dc.date.issued2019-
dc.identifier.citationThe American Journal of Human Genetics, 2019, v. 105 n. 2, p. 267-282-
dc.identifier.issn0002-9297-
dc.identifier.urihttp://hdl.handle.net/10722/280110-
dc.description.abstractSequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.-
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.cell.com/ajhg/home-
dc.relation.ispartofThe American Journal of Human Genetics-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectepilepsy-
dc.subjectseizures-
dc.subjectepileptic encephalopathy-
dc.subjectexome-
dc.subjectsequencing-
dc.titleUltra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals-
dc.typeArticle-
dc.identifier.emailBaum, LW: lwbaum@hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.authoritySham, PC=rp00459-
dc.description.naturepostprint-
dc.identifier.doi10.1016/j.ajhg.2019.05.020-
dc.identifier.scopuseid_2-s2.0-85069831549-
dc.identifier.hkuros308870-
dc.identifier.volume105-
dc.identifier.issue2-
dc.identifier.spage267-
dc.identifier.epage282-
dc.identifier.isiWOS:000478022200004-
dc.publisher.placeUnited States-
dc.identifier.issnl0002-9297-

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