De novo homozygous variant of the SCN1A gene in a patient with severe Dravet syndrome complicated by acute encephalopathy.

Variants in the SCN1A gene have been identified in epilepsy patients with widely variable phenotypes and they are generally heterozygous. Here, we report a homozygous missense variant, NM_001165963.4: c.4319C>T (p.Ala1440Val), in the SCN1A gene which seemed to occur de novo together with a gene conversion event. It's highly possible that this variant, although located in a critical functional domain of protein Nav1.1, depending on the nature of the amino acid substitution, may not cause the complete loss of protein function. And the accumulated effect by having this variant on both alleles results in a Dravet syndrome phenotype which is more severe than average. This first report of a de novo homozygous variant in the SCN1A gene, therefore, provides a clear illustration of a complex genotype-phenotype relationship.

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.

Mutation spectrum of ATP7B gene in pediatric patients with Wilson disease in Vietnam.

Background: Wilson disease (WD) is caused by mutations in the copper-transporting P-type adenosine triphosphatase encoded by the ATP7B gene. In this study, we screened and identified the ATP7B mutations among unrelated Vietnamese pediatric patients. Methods: One-hundred-thirteen pediatric patients with clinically diagnosed WD were recruited. DNA samples were extracted from peripheral blood. Mutations in the ATP7B gene were identified by Sanger sequencing. Results: Approximately 98% of the clinically diagnosed WD patients carried ATP7B mutations. A total of 35 different ATP7B variants were detected, including five novel mutations (L658P, L792P, T977K, IVS4 + 1G > A and IVS20 + 4A > G). Remarkably, this study revealed that S105* was the most prevalent variant (32.27%), followed by L1371P (9.09%), I1148T (7.27%), R778L (6.36%), T850I (5.45%), V176Sfs*28 and IVS14-2A > G (4.55%). Most ATP7B mutations were located in the exon 2 (37.73%), exon 16 (10.00%), exon 8 (9.55%), exon 20 (9.09%), exon 10 and exon 18 (5.45%), exon 14 (5.00%), exon 13 and intron 14 (4.55%). We developed a streamlined procedure to quickly characterize mutations in the ATP7B gene in the Vietnamese children, starting with sequencing exon 2 and subsequently to exons 8,10,13-16,18, and 20 to allow quick diagnosis of clinically suspected patients. Conclusion: The mutational spectrum and hotspots of ATP7B gene in the Vietnamese population were fairly different from other East Asian populations. A streamlined procedure was developed to screen exon 2 in ATP7B gene among suspected WD patients to reduce genetically diagnostic cost, to facilitate early detection and intervention in countries with limited resources.