Revisiting the clinical impact of variants in EFHC1 in patients with different phenotypes of genetic generalized epilepsy

Made available in DSpace on 2021-06-25T12:24:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) The most common form of genetic generalized epilepsy (GGE) is juvenile myodonic epilepsy (JME), which accounts for 5 to 10% of all epilepsy cases. The gene EFHC1 has been implicated as a putative cause of JME. However, it remains debatable whether testing for EFHC1 mutations should be included in the diagnostic epilepsy gene panels. To investigate the clinical utility of EFHC1 testing, we studied 125 individuals: 100 with JME and 25 with other GGEs. We amplified and sequenced all EFHC1 coding exons. Then, we predicted the pathogenicity or benign impact of the variants using the analyses proposed by the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP). Mutation screening revealed 11 missense variants in 44 probands with JME (44%) and one of the seven individuals with generalized tonic-clonic seizures on awakening (14%). Six of the 11 variants ( 54%) were classified as 'benign,' and the remaining variants were considered variants of uncertain significance (VUS). There is currently a limitation to test for genes that predispose an individual to complex, nonmonogenic phenotypes. Thus, we show suggestive evidence that EFHC1 testing lacks a scientific foundation based on the disputed nature of the gene-disease relationship and should be currently limited to research purposes. (C) 2020 Elsevier Inc. All rights reserved. Univ Campinas UNICAMP, Sch Med Sci, Dept Med Genet & Genom Med, Tessalia Vieira Camargo 126, BR-13083887 Campinas, SP, Brazil Univ Campinas UNICAMP, Sch Med Sci, Dept Neurol, Campinas, SP, Brazil Brazilian Inst Neurosci & Neurotechnol BRAINN, Campinas, SP, Brazil Fed Univ Alagoas UFAL, Inst Biol Sci & Hlth, Maceio, Alagoas, Brazil Sao Paulo State Univ UNESP, Sch Med, Dept Neurol & Psychiat, Botucatu, SP, Brazil Sao Paulo State Univ UNESP, Sch Med, Dept Neurol & Psychiat, Botucatu, SP, Brazil FAPESP: FAPESP: 2013/07559-3 CNPq: 143189/2009-3 CNPq: 403299/2016-0 CNPq: 309494/2014-1