Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice

Abstract

Although genetic revolution of recent years has vastly expanded a list of genes implicated in epilepsies, complex architecture of epilepsy genetics is still largely unknown, consequently, universally accepted workflows for epilepsy genetic testing in a clinical practice are missing. We present a comprehensive NGS-based diagnostic approach addressing both the clinical and genetic heterogeneity of disorders involving epilepsy or seizures. A bioinformatic panel of 862 epilepsy- or seizure-associated genes was applied to Mendeliome (4813 genes) or whole-exome sequencing data as a first stage, while the second stage included untargeted variant interpretation. Eighty-six consecutive patients with epilepsy or seizures associated with neurodevelopmental disorders and/or congenital malformations were investigated. Of the 86 probands, 42 harbored pathogenic and likely pathogenic variants, giving a diagnostic yield of 49%. Two patients were diagnosed with pathogenic copy number variations and 2 had causative mitochondrial DNA variants. Eleven patients (13%) were diagnosed with diseases with specific treatments. Besides, genomic approach in diagnostics had multiple additional benefits due to mostly non-specific, overlapping, not full-blown phenotypes and abilities to diagnose novel and ultra rare epilepsy-associated diseases. Likely pathogenic variants were identified in SOX5 gene, not previously associated with epilepsy, and UBA5, a recently associated with epilepsy gene.

Clinical and molecular diagnostic study of 320 Chinese children with epilepsy by Genome Sequencing

“…The diagnostic yield of previous studies on epilepsy was about 18%-49% [34][35][36][37][38]. The patients with epilepsy in different studies were different, and the filtering and interpretation methods for the variants were different.…”

Clinical exome sequencing identifies two novel mutations of the SCN1A and SCN2A genes in Moroccan patients with epilepsy: a case series

“…However, given the large number of genetic diseases with epilepsy as a symptom and given that gene panels developed by each laboratory differ greatly, CES is becoming an effective common molecular diagnostic tool for individuals with a heterogeneous phenotype. In addition, epilepsy gene panels are multiple and so far there are no next-generation sequencing (NGS) guidelines for patients with epilepsy [8]. Currently, there is a huge diversity in the number and composition of genes of the different epilepsy panels commercially available [9–12].…”

Clinical next generation sequencing reveals an H3F3A gene as a new potential gene candidate for microcephaly associated with severe developmental delay, intellectual disability and growth retardation

“…A recent study [3], employing molecular karyotyping and exome sequencing, improved diagnostic rates to 58.0% with primary microcephaly, 27.0% with secondary microcephaly, and to 15.0% in patients with unknown onset. Moreover, whole exome sequencing in the clinical setting may identify not only mutations in genes already known to be associated with investigated phenotypes, but also discover new potential genes and mechanisms for human disorders [5,6]. In this study, we describe a new association between microcephaly accompanied with severe developmental delay and intellectual disability and a potentially new gene H3F3A involved in maintaining heterochromatin and telomeric integrity.…”