Genetic analysis using targeted exome sequencing of 53 Vietnamese children with developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEE) refers to a group of rare and severe neurodevelopmental disorders where genetic etiologies can play a major role. This study aimed to elucidate the genetic etiologies of a cohort of 53 Vietnamese patients with DEE. All patients were classified into known electroclinical syndromes where possible. Exome sequencing (ES) followed by a targeted analysis on 294 DEE-related genes was then performed. Patients with identified causative variants were followed for 6 months to determine the impact of genetic testing on their treatment. The diagnostic yield was 38.0% (20/53), which was significantly higher in the earlier onset group (<12 months) than in the later onset group (≥12 months). The 19 identified variants belonged to 11 genes with various cellular functions. Genes encoding ion channels especially sodium voltage-gated channel were the most frequently involved. Most variants were missense variants and located in key protein functional domains. Four variants were novel and four had been reported previously but in different phenotypes. Within 6 months of further follow-up, treatment changes were applied for six patients based on the identified disease-causing variants, with five patients showing a positive impact. This is the first study in Vietnam to analyze the genetics of DEE. This study confirms the strong involvement of genetic etiologies in DEE, especially early onset DEE. The study also contributes to clarify the genotype-phenotype correlations of DEE and highlights the efficacy of targeted ES in the diagnosis and treatment of DEE.

Genotype and phenotype characteristics of West syndrome in 20 Vietnamese children: Two novel variants detected by next-generation sequencing.

BACKGROUND: In children with West syndrome (WS), whose treatment is challenging due to drug resistance and poor prognosis, investigation of genetic etiology and genotype-phenotype characteristics might assist in treatment optimization and genetic counseling. OBJECTIVE: In this study, we aimed to present the results of genetic analysis and the corresponding phenotypes in a cohort of twenty children with WS in Vietnam. METHODS: Our study was designed as a single-institution retrospective case series, in which consecutive sampling was used to select WS children having undergone genetic testing. Identified variants were investigated individually or as a variant combination by bioinformatics platforms. Clinical data were used to establish the genotype-phenotype correlation and compare clinical characteristics between groups of genetic causes and unknown causes. RESULTS: Genetic testing identified at least one variant in 17/20 children. According to ACMG 2015, of all variants, one variant (3.9%) was classified as a benign variant, 16 variants (61.5%) were variants of uncertain significance, 4 (15.4%) were likely pathogenic variants, and 5 (19.2%) were pathogenic variants. These 26 variants belonged to 21 genes, of which eight candidate genes were CREBBP, MED25, HDAC8, SCN3A, ABCD1, TSC2, COL4A1, and NDUFA10. Two novel variants of SCN3A and TSC2 were found. Predicted pathogenic variant combinations were identified in two cases. Compared to three children of unknown etiology, five children with genetic causes had a higher rate of abnormal brain structures, developmental delay, and treatment resistance. CONCLUSIONS: WS has a genetically heterogeneous etiology, and some cases might be polygenically susceptible. Our findings expand the disease's genotype-phenotype spectrum and support previous literature results that genetic etiology poses an unfavorable outcome in WS.