Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry

Abstract

Brugada syndrome (BrS) is a heritable disease that results in sudden cardiac death. In the exome/genomic era, certain reported pathogenic variants in some genetic diseases have been reclassified as benign owing to their high frequency in some ancestries. In the present study, we comprehensively reassessed all previously reported pathogenic variants of BrS. We collected all pathogenic variants of BrS reported in the Human Gene Mutation Database and ClinVar throughout April 2017. We compared the minor allele frequency (MAF) of each variant among different ancestries by searching public whole-genome and exome databases. After considering the maximum credible allele frequency, variants with a MAF ≥ 0.001 were considered to be of questionable pathogenicity. We also investigated the percentage of SCN5A variants with a MAF ≥ 0.001 in 124 BrS patients from the Han Chinese population. We collected a total of 440 BrS variants, of which 18 had a MAF ≥ 0.001. There was a greater percentage of non-SCN5A variants with a MAF ≥ 0.001 than of SCN5A variants (21.8 versus 1.6%, p < 0.0001). There were fewer frameshift and nonsense mutations than missense mutations (0.9 versus 5.6%, p = 0.032). Of the 18 variants, 14 (77.8%) were present only in the reference Asian population. In our cohort, we identified two SCN5A variants (p.A226V and p.V1340I) with MAFs ≥ 0.001 (0.45%). In conclusion, ancestral differences are important when considering the pathogenicity of BrS variants, especially in the case of missense variants and non-SCN5A variants, which may be pathogenic in some ancestries but only disease-predisposing in others.

EF hand‐like motif mutations of Nav1.4 C‐terminus cause myotonic syndrome by impairing fast inactivation

“…Electrophysiological analysis of M1875T in Nav1.5 showed disrupted fast inactivation, which is similar to a functional abnormality with our mutations . Furthermore, p.K1872N, which is located near the mutations in this study, in helix αV of EFL in Nav1.5, was reported as a pathogenic mutation of Brugada syndrome . This evidence strengthens the significance of EFL for Nav channel function.…”

Brugada Syndrome: Oligogenic or Mendelian Disease?

“…It has been suggested that post-translational modifications, such as a defect in the splicing process [93] or trafficking [94,95], or a modification in phosphorylation, methylation, or acetylation [96], could explain alterations in the function of the channel encoded by SCN5A in the absence of mutations in this gene itself. Also, the predicted phenotypic effect of a particular variant should take into consideration that ancestry can affect the pathogenicity of a particular variant [97]. Thus, there are several factors that can contribute to channel function, or dysfunction, other than mutations in the SCN5A gene itself that encodes for the Na V 1.5 protein.…”

Clinical impact of rare variants associated with inherited channelopathies: a 5-year update

“…Thus, periodic reclassification of rare variants is recommended before clinical translation; as of yet, there is no concrete timeframe for this process. Currently, only a few reports have addressed this novel challenge (Bennett et al 2019;Campuzano et al 2020a, b;Chen et al 2018;Denham et al 2018;Salfati et al 2019;VanDyke et al 2020) despite the impact reclassifications can have improving psychological outcomes and risk stratification while promoting personalized management (Macklin et al 2019;Tsai et al 2019). In this study, we updated data to reclassify rare variants associated with the most common ICC, classified 5 years ago following ACMG recommendations, and potential clinical impact.…”