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Characteristics of KCNQ 2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy
Author(s) -
Goto Ayako,
Ishii Atsushi,
Shibata Mami,
Ihara Yukiko,
Cooper Edward C.,
Hirose Shinichi
Publication year - 2019
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16314
Subject(s) - missense mutation , genetics , biology , phenotype , epilepsy , gene , candidate gene , genetic variation , neuroscience
Objective Pathogenic variants of KCNQ 2 , which encode a potassium channel subunit, cause either benign (familial) neonatal epilepsy—B(F) NE )—or KCNQ 2 encephalopathy ( KCNQ 2 DEE ). We examined the characteristics of KCNQ 2 variants. Methods KCNQ 2 pathogenic variants were collected from in‐house data and two large disease databases with their clinical phenotypes. Nonpathogenic KCNQ 2 variants were collected from the Genome Aggregation Database (gnom AD ). Pathogenicity of all variants was reevaluated with clinical information to exclude irrelevant variants. The cumulative distribution plots of B(F) NE , KCNQ 2 DEE , and gnom AD KCNQ 2 variants were compared. Several algorithms predicting genetic variant pathogenicity were evaluated. Results A total of 259 individuals or pedigrees with 216 different pathogenic KCNQ 2 variants and 2967 individuals with 247 different nonpathogenic variants were deemed eligible for the study. Compared to the distribution of nonpathogenic variants, B(F) NE and KCNQ 2 DEE missense variants occurred in five and three specific KCNQ 2 regions, respectively. Comparison between B(F) NE and KCNQ 2 DEE sets showed that B(F) NE missense variants frequently localized to the intracellular domain between S2 and S3, whereas those of KCNQ 2 DEE were more frequent in S6, and its adjacent pore domain, as well as in the intracellular domain between S6 and helix A. The scores of Protein Variation Effect Analyzer ( PROVEAN ) and Percent Accepted Mutation ( PAM ) 30 prediction algorithms were associated with phenotypes of the variant loci. Significance Missense variants in the intracellular domain between S2 and S3 are likely to cause B(F) NE , whereas those in S6 and its adjacent regions are more likely to cause KCNQ 2 DEE . With such regional specificities of variants, PAM 30 is a helpful tool to examine the possibility that a novel KCNQ 2 variant is a B(F) NE or KCNQ 2 DEE variant in genetic analysis.