Open AccessGene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy
Author(s) -
Fung CheukWing,
Kwong Anna KaYee,
Wong Virginia ChunNei
Publication year - 2017
Publication title -
epilepsia open
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.247
H-Index - 16
ISSN - 2470-9239
DOI - 10.1002/epi4.12055
Subject(s) - epilepsy , medicine , medical genetics , cohort , dravet syndrome , phenotype , genetic heterogeneity , genetic testing , clinical significance , genetics , bioinformatics , gene , biology , pediatrics , psychiatry
Summary Objective Epileptic encephalopathy ( EE ) is a heterogeneous condition associated with deteriorations of cognitive, sensory and/or motor functions as a consequence of epileptic activity. The phenomenon is the most common and severe in infancy and early childhood. Genetic‐based diagnosis in EE patients is challenging owing to genetic and phenotypic heterogeneity of numerous monogenic disorders and the fact that thousands of genes are involved in neurodevelopment. Therefore, high‐throughput next‐generation sequencing ( NGS ) was used to investigate the genetic causes of non‐syndromic cryptogenic neonatal/infantile EE ( NIEE ). Methods We have selected a cohort of 31 patients with seizure cryptogenic NIEE and seizure onset before 24 months. All investigations including metabolic work‐up, were negative. Using NGS, we distinguished a panel of 430 epilepsy‐associated genes by NGS was utilized to identify possible pathogenic variants in the patients. Segregation analysis and multiple silico analysis prediction tools were used for pathogenicity assessment. The identified variants were classified as “pathogenic,” “likely pathogenic” and “uncertain significance,” according to the American College of Medical Genetics ( ACMG ) guidelines. Results Pathogenic or likely pathogenic variants were identified in six genes ( ALG 13 [1], CDKL 5 [2] , KCNQ 2 [2] , PNPO [1] , SCN 8A [1] , SLC 9A6 [2]) in 9 NIEE patients (9/31; 29%). Variants of uncertain significance ( VUS ) were found in DNM 1 and TUBA 8 in 2 NIEE patients (2/31; 6%). Most phenotypes in our cohort matched with those reported cases. Significance The diagnostic rate (29%) of pathogenic and likely pathogenic variants was comparable to the recent studies of early‐onset epileptic encephalopathy, indicating that gene panel analysis through NGS is a powerful tool to investigate cryptogenic NIEE in patients. Six percent of patients had neurometabolic disorders. Some of our diagnosed cases illustrated that successful molecular investigation may allow a better treatment strategy and avoid unnecessary and even invasive investigations. Functional analysis could be performed to further study the pathogenicity of the VUS identified in DNM 1 and TUBA 8 .