Pathogenic significance of SCN1A splicing variants causing Dravet syndrome: Improving diagnosis with targeted sequencing for variants by in silico analysis

Abstract

Objectives: Genetic heterogeneity of epileptic encephalopathy (IEE) mandates the use of gene-panels for diagnosis. Patients and Methods: A 36-gene-panel next-generation sequencing was applied for IEE in two Iranian families. A literature search was performed using keywords to identify reported splicing mutations in SCN1A and perform genotype-phenotype correlation. Results: An update of splicing mutations revealed 147 variants with 65.75 of them de novo mutations. Most of the familial variants were of parental origin. The structure of the protein was often affected in the linker and transmembrane segments. 92 of intronic variants were pathogenic. A de novo heterozygous mutation was found in the first patient, but not in her sibling and parents. In the second family, a novel de novo heterozygous mutation was found at position c.1210insT leading to a truncated protein. Conclusion: Gene-panel sequencing is helpful for reducing the time and cost, guiding early treatment, and estimating the recurrence risks. The importance of characterization of intronic variants was noticed; though bioinformatics analysis of novel intronic variants should be of concern for rapid reporting the pathogenic effect of variants. © 2018 Elsevier B.V