Novel and de novo mutations in pediatric refractory epilepsy

Abstract

Pediatric refractory epilepsy is a broad phenotypic spectrum with great genetic heterogeneity. Next-generation sequencing (NGS) combined with Sanger sequencing could help to understand the genetic diversity and underlying disease mechanisms in pediatric epilepsy. Here, we report sequencing results from a cohort of 172 refractory epilepsy patients aged 0–14 years. The pathogenicity of identified variants was evaluated in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria. We identified 43 pathogenic or likely pathogenic variants in 40 patients (23.3%). Among these variants, 74.4% mutations (32/43) were de novo and 60.5% mutations (26/43) were novel. Patients with onset age of seizures ≤12 months had higher yields of deleterious variants compared to those with onset age of seizures > 12 months (P = 0.006). Variants in ion channel genes accounted for the greatest functional gene category (55.8%), with SCN1A coming first (16/43). 81.25% (13/16) of SCN1A mutations were de novo and 68.8% (11/16) were novel in Dravet syndrome. Pathogenic or likely pathogenic variants were found in the KCNQ2, STXBP1, SCN2A genes in Ohtahara syndrome. Novel deleterious variants were also found in West syndrome, Doose syndrome and glucose transporter type 1 deficiency syndrome patients. One de novo MECP2 mutation were found in a Rett syndrome patient. TSC1/TSC2 variants were found in 60% patients with tuberous sclerosis complex patients. Other novel mutations detected in unclassified epilepsy patients involve the SCN8A, CACNA1A, GABRB3, GABRA1, IQSEC2, TSC1, VRK2, ATP1A2, PCDH19, SLC9A6 and CHD2 genes. Our study provides novel insights into the genetic origins of pediatric epilepsy and represents a starting-point for further investigations into the molecular pathophysiology of pediatric epilepsy that could eventually lead to better treatments.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0392-5) contains supplementary material, which is available to authorized users.

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

“…Non-functional channel (Nabbout et al, 2003;Ohmori et al, 2006;Usluer et al, 2016 (Claes et al, 2001;Nabbout et al, 2003;Fukuma et al, 2004;Harkin et al, 2007;Depienne et al, 2008;Orrico et al, 2009;Zuberi et al, 2011;Wang et al, 2012;Xu et al, 2014;Esterhuizen et al, (Nabbout et al, 2003;Ohmori et al, 2006;Depienne et al, 2008;Mak et al, 2011;Wang et al, 2012;Lindy et al, (Nabbout et al, 2003;Wang et al, 2012;Liu et al, 2018) P281L DI (S5-S6) Missense DS Moderate mental retardation (Depienne et al, 2008;Gokben et al, 2017;Lindy et al, (Claes et al, 2003;Marini et al, 2007;Sun et al, 2010;Zuberi et al, 2011;Lemke et al, 2012;Rilstone et al, 2012;Wang et al, 2012;Xu et al, 2014;Djeḿiéet al, 2016;Haginoya et al, (Nabbout et al, 2003;Ohmori et al, 2006;Allen et al, 2016 (Claes et al, 2003;Ohmori et al, 2006)…”

Functional genomics of epilepsy-associated mutations in the GABAA receptor subunits reveal that one mutation impairs function and two are catastrophic

“…Indeed, all ␤3 mutations would be expressed in these subtypes, and as such, the effects of the ␤3 D120N , ␤3 T157M , and ␤3 Y302C on extrasynaptic receptors also need to be considered, particularly when the ␤3 T157M mutation has been reported to have little effect when expressed in the ␣5␤3␥2 subtype (8). It is also possible that the ␤3 S254F mutation is not truly pathogenic in itself; however, this mutation has been subsequently identified de novo in another patient and is therefore very unlikely not to be pathogenic (46). (40,41) showing the ␤3 S254 or ␤1 S254 mutant residues in the two different subunit locations of the second ␤3 subunit (left) and fourth ␤3 subunit (right).…”

Clinical and genetic characteristics of patients with Doose syndrome

“…Given that the male‐to‐female ratio of MAE is 2‐3:1 and that 14%‐32% of patients have a family history of epileptic seizures or EEG abnormalities, researchers have long suspected genetic predisposition 1,5 . So far, 11 genes, SCN1A , 6 SCN1B , 7 CACNA1H , 8 SLC2A1 , 9 GABRG2 , 10 CHD2 , 10 SLC6A1 , 11 STX1B , 12 GABRB3 , 13 SYNGAP1 , 14 and WDR45 , 15 have been reported to be causative for MAE. This suggests that MAE is highly heterogeneous, as Doose originally predicted.…”