ExACtly zero or once

Abstract

Objective:To assist the interpretation of genomic data for common epilepsies, we asked whether variants implicated in mild epilepsies in autosomal dominant families are present in the general population.Methods:We studied 12 genes for the milder epilepsies and identified published variants with strong segregation support (de novo germline mutation or ≥4 affected family members). These variants were checked in the Exome Aggregation Consortium (ExAC), a database of genetic variation in over 60,000 individuals. We subsequently evaluated variants in these epilepsy genes that lacked strong segregation support. To determine whether the findings in epilepsies were representative of other diseases, we also assessed the presence of variants in other dominant neurologic disorders (e.g., CADASIL).Results:Published epilepsy variants with strong segregation support (n = 65) were absent (n = 61) or present once (n = 4) in ExAC. By contrast, of 46 published epilepsy variants without strong segregation support, 8 occurred recurrently (2–186 times). Similarly, none of the 45 disease-associated variants from other neurologic disorders with strong segregation support occurred more than once in ExAC. Reanalysis using the larger ExAC V2 plus gnomAD reference cohort showed consistent results.Conclusions:Variants causing autosomal dominant epilepsies are ultra-rare in the general population. Variants observed more than once in ExAC were only found among reports without strong segregation support, suggesting that they may be benign. Clinicians are increasingly faced with the interpretation of genetic variants of unknown significance. These data illustrate that variants present more than once in ExAC are less likely to be pathogenic, reinforcing the valuable clinical role of ExAC.

Molecular Genetic Characterization of Patients With Focal Epilepsy Using a Customized Targeted Resequencing Gene Panel

“…Only nonsense, nonsynonymous, splice-site and frameshift variants were further evaluated. Variants presented in the Thousand Genome Project (TGP, http://www.internationalgenome.org/ ), the Exome Variant Server (EVS, http://evs.gs.washington.edu/EVS/ ), more than 1 hit in the Board Institute Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ), and more than five hits in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org ) were excluded ( 37 ). Four prediction programs, including SIFT (v1.03) ( 38 ), PolyPhen-2 (v2.2.2 build r394) ( 39 ), MutationTaster 2 ( 40 ), and Combined Annotation Dependent Depletion (CADD v1.2)( 41 ) were used to prioritize variants.…”

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

“…DI (S4-S5) Missense DS Myoclonic seizures Generalized spikes or spike-and-wave complexes in the interictal (EEG) (Morimoto et al, 2006) R377Q DI (S5-S6) Missense GEFS+ Generalized tonic-clonic seizures (Zucca et al, 2008;Xu et al, 2015;Cetica et al, 2017;Lindy et al, (Escayg et al, 2001;Weiss et al, 2003;Combi et al, 2009;Orrico et al, 2009;Wang et al, 2012;Lee et al, 2014;Lal et al, (Annesi et al, 2003;Orrico et al, 2009;Bechi et al, 2015;Bennett et al, (Escayg et al, 2001;Gargus and Tournay, 2007;Yordanova et al, 2011;Rilstone et al, 2012;Cestèle et al, 2013;Lal et al, 2016) V1353L DIII (S5) Missense PEFS+ GEFS+ Non-functional channel (Wallace et al, 2001;Lossin et al, 2003;Bennett et al, (Usluer et al, 2016) I91T N-terminal Missense DS Frontal-dominant spike-waves complex (EEG) (Sun et al, 2008;Xu et al, 2014) G96EfsX24 N-terminal FrameShift NR Genetic generalized epilepsy with intellectual disability (Fry et al, 2016) R101Q N-terminal Missense DS SMEB GEFS+ PEFS+ Psychomotor retardation (Fukuma et al, 2004;Harkin et al, 2007;Marini et al, 2007;Depienne et al, 2008;Sun et al, 2010;Zuberi et al, 2011;Wang et al, 2012;Tonekaboni et al, 2013;…”

Variants inCHRNB2andCHRNA4Identified in Patients with Insular Epilepsy

“…26,27 At the moment, the evidence available to clinically assess the pathogenicity of the p. Thr26Met (c.77C>T) missense variant in CHRNB2 is conflicting or insufficient. Although it has been suggested that variants found in more than one heterozygote in population databases are less likely to be pathogenic, 28 we provide functional evidence that indicates that it could play a role in the disease. Also, it is important to note that Clinvar submitters mostly rely on existing literature to assess variant pathogenicity.…”