Prevalence and electrophysiological phenotype of rare SCN5A genetic variants identified in unexplained sudden cardiac arrest survivors

Abstract

Aims To determine the prevalence and in vitro electrophysiological (EP) phenotype of ultra-rare SCN5A variants of uncertain significance (VUS) identified in unexplained sudden cardiac arrest (SCA) survivors. Methods and results Retrospective review of 73 unexplained SCA survivors was used to identify all patients that underwent a form of genetic testing that included comprehensive SCN5A analysis. Ultra-rare SCN5A variants (minor allele frequency < 0.005) were adjudicated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Variants designated as VUS were expressed heterologously and characterized using the whole-cell patch clamp technique. Overall, 60/73 (82%; the average age at SCA 28 ± 12 years) unexplained SCA survivors had received SCN5A genetic testing. Of these, 5/60 (8.3%) had an ultra-rare SCN5A variant. All SCN5A variants were classified as VUS. Whereas the single SCN5A VUS (p.Asp872Asn-SCN5A) identified in an unexplained SCA survivor with PR interval prolongation and inferior early repolarization conferred a loss-of-function phenotype (46.2% reduction in peak current density; 16 ms slower recovery from inactivation), the four other SCN5A VUS (p.Glu30Gly-SCN5A, p.Gln245Lys-SCN5A, p.Pro648Leu-SCN5A, and p.Glu1240Gln-SCN5A) identified in unexplained SCA survivors without early repolarization/conduction delay were indistinguishable from wild-type Nav1.5 channels. Conclusion In the absence of a phenotype(s) potentially attributable to sodium channel dysfunction, all SCN5A VUS identified in unexplained SCA survivors conferred a wild-type EP phenotype in vitro. As the background rate of SCN5A genetic variation is not trivial, great care must be taken to avoid prioritizing genotype over phenotype when attempting to ascertain the root cause of an individual's SCA.

A novel functional variant residing outside the SCN5A-encoded Nav1.5 voltage-sensing domain causes multifocal ectopic Purkinje-related premature contractions

“…As described previously, the standard whole-cell patch-clamp technique was used to measure SCN5A wild-type (WT) and p.Gln419Pro-SCN5A (Q419P) sodium currents at room temperature (22-24 o C) with the use of an Axopatch 200B amplifier, Digidata 1440A and pclamp 10 software 13,14 . All data points are shown as the mean values.…”

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

“…There has not yet been a consensus curation for ERS. SCN5A variants with loss‐of‐function (determined by patch clamping expression studies) have been identified in 2–10% of patients with ERS, the patients showed signs of conduction slowing, supporting a depolarization phenotype 297–299 . Two paediatric ERS cases have been identified with a duplication and a de novo missense variant in KCND3 responsible for I TO 300,301 .…”

“…SCN5A variants with loss-of-function (determined by patch clamping expression studies) have been identified in 2-10% of patients with ERS, the patients showed signs of conduction slowing, supporting a depolarization phenotype. [297][298][299] Two paediatric ERS cases have been identified with a duplication and a de novo missense variant in KCND3 responsible for I TO . 300,301 Furthermore, a recent general population GWAS has associated ERP with a genome-wide significant SNP tagging the KCND3 locus (encoding the I To current alpha subunit), suggesting the possibility of polygenic heritability.…”

Electrocardiographic Features in SCN5A Mutation-Positive Patients with Brugada and Early Repolarization Syndromes: A Systematic Review and Meta-Analysis

“…Recent work has proposed polygenic risk scores based on the mutation type in BrS [21]. In this study we focused on SCN5A variants, the most commonly associated variant in ERS [22]. KCNJ8, ABCC9, KCNE5, DPP10, CACNA1C, CACNB2B, CACNA2D1, SCN5A, SCN10A are all linked with ERS [23] but a polygenic risk score for ERS is yet to be determined or implemented.…”