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.