Functional Characterization of SCN10A Variants in Several Cases of Sudden Unexplained Death

• NCJ Number: 254255
• Journal: Forensic Science International Volume: 301 Dated: August 2019 Pages: 289-298
• Author(s): Ivan Gando; Nori Williams; Glenn I. Fishman; Barbara A Sampson; Yingying Tang; William A Coetzee
• Date Published: August 2019
• Length: 10 pages
• Grant Number(s): 2015-DN-BX-K017
• Agencies: NIJ-Sponsored
• Publication Type: Research (Applied/Empirical); Report (Study/Research); Report (Grant Sponsored); Program/Project Description

Annotation

Since the New York City Office of Chief Medical Examiner has identified five SCN10A variants of uncertain significance in six separate cases within a cohort of 330 sudden unexplained death events (The gene product of SCN10A is the Nav1.8 sodium channel), the purpose of the current study was to characterize the effects of these variants on Nav1.8 channel function to provide better information for the reclassification of these variants.

Abstract

Multiple genome-wide association studies (GWAS) and targeted gene sequencing have identified common variants in SCN10A in cases of PR and QRS duration abnormalities, atrial fibrillation and Brugada syndrome. The current study performed patch clamp studies to assess the effects of the variants on whole-cell Nav1.8 currents. It also performed RNA-seq analysis and immunofluorescence confocal microcopy to determine Nav1.8 expression in heart. The findings indicate that four of the five rare 'variants of unknown significance' (L388M, L867F, P1102S and V1518I) are associated with altered functional phenotypes. The R756W variant behaved similar to wild-type under the experimental conditions. Researchers failed to detect Nav1.8 protein expression in immunofluorescence microscopy in rat heart. Furthermore, RNA-seq analysis failed to detect full-length SCN10A mRNA transcripts in human ventricle or mouse specialized cardiac conduction system, suggesting that the effect of Nav1.8 on cardiac function is likely to be extra-cardiac in origin. This project demonstrated that four of five SCN10A variants of uncertain significance identified in unexplained death have deleterious effects on channel function. These data extend the genetic testing of SUD cases; however, significantly more clinical evidence is needed to satisfy the criteria needed to associate these variants with the onset of SUD. (publisher abstract modified)