Novel mutations and phenotypes of epilepsy‐associated genes in epileptic encephalopathies

Abstract

Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next-generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty-three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance. Twelve variants were initially assessed as uncertain significance by ACMG, among which 3 were considered causative and 3 others were considered possibly causative after analysis of clinical concordance. In total, 24 variants were identified as putatively causative, among which 19 were novel findings. SCN1A mutations were identified in 50% of patients with Dravet syndrome. TSC1/TSC2 mutations were detected in 66.7% of patients with tuberous sclerosis. STXBP1 mutations were the main findings in patients with West syndrome. Mutations in SCN2A, KCNT1, KCNQ2 and CLCN4 were identified in patients with epileptic infantile with migrating focal seizures; among them, KCNQ2 and CLCN4 were first identified as potential causative genes. Only one CHD2 mutation was detected in patients with Lennox-Gastaut syndrome. This study highlighted the utility of targeted NGS in genetic diagnoses of epileptic encephalopathies and a comprehensive evaluation of the pathogenicity of variants based on ACMG scoring and assessment of clinical concordance. Epileptic encephalopathies differ in genetic causes, and the genotype-phenotype correlations would provide insights into the underlying pathogenic mechanisms.

Genotype and phenotype analysis using an epilepsy‐associated gene panel in Chinese pediatric epilepsy patients

“…A test with a panel of 480 epilepsy‐related genes provided a diagnostic yield of 27.7% in all included patients. The EE patients in our group had a higher yield (73.1%) than was reported in previous investigations . The patient selection process and small size of the EE patient pool might have influenced the yield rates.…”

“…Genetic pathogenic variants have been identified as the most important factors in epilepsy syndromes. Hence, targeted genetic sequencing studies have been extensively and intensively applied in epilepsy syndromes, especially epileptic encephalopathy (EE) in infants . It also remains important to evaluate the genetic etiology of epilepsy cases that occur in subjects with no known family history who were therefore previously considered idiopathic.…”

DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect

“…A gene panel was designed for targeted sequencing of 483 genes that are possibly associated with epilepsy to uncover disease-causing variants ( Supplementary Table S1) (Zhou et al, 2018). Genes potentially associated with focal epilepsies in the panel included CHRNA2, CHRNA4, CHRNB2, CNTNAP2, DEPDC5, FLNA, GABRG2, GRIN2A, KCNQ2, KCNQ3, KCNT1, LGI1, MECP2, NPRL2, NPRL3, PCDH19, POLG, PRIMA1, PRRT2, RELN, SCN1A, SCN1B, SCN2A, SLC2A1, SRPX2, SYN1, TBC1D24, TSC1, and TSC2.…”

Encefalopatía epiléptica infantil en un paciente colombiano con una variante patogénica de novo en el gen STXBP1

“…Las encefalopatías por STXBP1 son causadas por diferentes tipos de mutaciones, se han descrito algunos puntuales, microdeleciones y/o mutaciones que afectan los sitios de splicing. 14,15 Las encefalopatías epilépticas causadas por…”