Variants in BRWD3 associated with X-linked partial epilepsy without intellectual disability

Abstract

Aims: Etiology of the majority patients with idiopathic partial epilepsy (IPE) remains elusive. We thus screened the potential disease-associated variants in the patients with IPE.

Methods: Trios-based whole exome sequencing was performed in a cohort of 320 patients with IPE. Frequency and molecular effects of variants were predicted.

Results: Three novel BRWD3 variants were identified in five unrelated cases with IPE, which were four male cases and one female case. The variants included two recurrent missense variants (c.836C>T/p.Thr279Ile and c.4234A>C/p.Ile1412Leu) and one intronic variant close to splice site (c.2475 + 6A>G). The two missense variants were located in WD40 repeat domain and bromodomain, respectively. They were predicted to be damaging by silico tools and change hydrogen bonds with surrounding amino acids. The frequency of mutant alleles in this cohort was significantly higher than that in the controls of East Asian and all population of gnomAD. All these variants were inherited from the asymptomatic mothers. Four male cases presented frequent seizures at onset, while the female case only had two fever-triggered seizures. They showed good responses to valproate and lamotrigine, then finally became seizure free. All the cases had no intellectual disability. Further analysis demonstrated that all previously reported destructive variants of BRWD3 caused intellectual disability, while missense variants located in WD40 repeat domains and bromodomains of BRWD3 were associated with epilepsy.

Conclusion: BRWD3 gene is potentially associated with X-linked partial epilepsy without intellectual disability. The genotypes and locations of BRWD3 variants may explain for their phenotypic variation.

Keywords: BRWD3 gene; epilepsy; intellectual disability; whole-exome sequencing.

FIGURE 1

Genetic data on the patients with BRWD3 variants. (A) Pedigrees of the five cases with BRWD3 variants and their corresponding phenotypes. (B) DNA sequence chromatograms of the BRWD3 variant. Arrows indicate the positions of the variants

FIGURE 2

Schematic illustration of BRWD3 variants. (A) Phylogenetic conservation of the Thr279 and Ile1412 (highlighted in red). These residues were conserved between species during evolution. (B) Schematic diagram of BRWD3 and the localization of the missense variants of BRWD3 identified in previous reports and in this study. (C) Hydrogen bond changes of mutants Thr279Ile and Ile1412Leu

FIGURE 3

Ictal and interictal EEG in the cases with BRWD3 variants. (A) EEG of case 1 detected partial seizures originated from left frontal region (red box indexed the seizure onset) (obtained at age of 9). (B) EEG of case 2 showed right centrotemporal discharges (black line) (at the age of 4.5 years). (C) EEG of case 5 indicated right temporal spike/sharp‐slow waves (black line) (obtained at age of 12 years)