Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals.

TitleSub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals.
Publication TypeJournal Article
Year of Publication2021
Corporate AuthorsEpi25 Collaborative. Electronic address:, Epi25 Collaborative
JournalAm J Hum Genet
Date Published2021 06 03
KeywordsCase-Control Studies, Cohort Studies, Epilepsy, Exome, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Humans, Phenotype, Whole Exome Sequencing

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Alternate JournalAm J Hum Genet
PubMed ID33932343
PubMed Central IDPMC8206159
Grant ListR03 NS108145 / NS / NINDS NIH HHS / United States
TL1 TR001875 / TR / NCATS NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States
UM1 HG008895 / HG / NHGRI NIH HHS / United States