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Background: A large number of SCN5A variants have been reported to underlie Brugada syndrome (BrS). However, the evidence supporting individual variants is highly heterogeneous. Objective: We systematically re‐evaluated all SCN5A variants reported in BrS using the 2015 American college of medical genetics and genomics and the association for molecular pathology (ACMG‐AMP) guidelines. Methods: A PubMed/Embase search was performed to identify all reported SCN5A variants in BrS. Standardized bioinformatic re‐analysis (SIFT, PolyPhen, Mutation Taster, Mutation assessor, FATHMM, GERP, PhyloP, and SiPhy) and re‐evaluation of frequency in the gnomAD database were performed. Fourteen ACMG‐AMP rules were deemed applicable for SCN5A variant analysis. Results: Four hundred and eighty unique SCN5A variants were identified, the majority of which 425 (88%) were coding variants. One hundred and fifty‐six of 425 (37%) variants were classified as pathogenic/likely pathogenic. Two hundred and fifty‐eight (60%) were classified as variants of uncertain significance, while a further 11 (3%) were classified as benign/likely benign. When considering the subset of variants that were considered "null" variants separately, 95% fulfilled criteria for pathogenicity/likely pathogenicity. In contrast, only 17% of missense variants fulfilled criteria for pathogenicity/likely pathogenicity. Importantly, however, only 25% of missense variants had available functional data, which was a major score driver for pathogenic classification. Conclusion: Based on contemporary ACMG‐AMP guidelines, only a minority of SCN5A variants implicated in BrS fulfill the criteria for pathogenicity or likely pathogenicity. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) continues to be the most common cause of death worldwide, and cardiac arrhythmias account for approximately one half of these deaths. The morbidity and mortality from CVD have been reduced significantly over the past few decades; however, disparities in racial or ethnic populations still exist. This review is based on available literature to date and focuses on known cardiac channelopathies and other inherited disorders associated with sudden cardiac death in African American/Black subjects and the role of epigenetics in phenotypic manifestations of CVD, and illustrates existing disparities in treatment and outcomes. The review also highlights the knowledge gaps that limit understanding of the manifestation of phenotypic abnormalities across racial or ethnic groups and discusses disparities associated with device underuse in the management of patients at risk for sudden cardiac death. We discuss factors related to reports in the United States, that the overall mortality attributed to CVD and the number of out-of-hospital cardiac arrests are higher among African American/Black subjects when compared with other racial or ethnic groups. African American/Black subjects are disproportionally affected by CVD, including cardiac arrhythmias and sudden cardiac death, thus highlighting a major concern in this population that remains underrepresented in clinical trials with limited genetic testing and device underuse. The proposed solutions include (1) early identification of genetic variants, which is crucial in tailoring a preventive management strategy; (2) inclusion of diverse racial or ethnic groups in clinical trials; (3) compliance with guideline-directed medical treatment and referral to cardiovascular subspecialists; and (4) training and mentoring of underrepresented junior faculty in cardiovascular health disparities research.

Aims: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Na v 1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Na v 1.5) in ARVD/C., Methods and Results: We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 ± 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient's peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of Na V 1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60% male, 34.8 ± 13.7 years, 52% desmosomal mutation-carriers). Five (1.8%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 ± 15 vs. 94 ± 14 ms, P < 0.01) and all SCN5A variant carriers had major structural abnormalities on cardiac imaging., Conclusions: Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Na v 1.5 and N-Cadherin clusters at junctional sites. This suggests that Na v 1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Na v 1.5 dysfunction causes cardiomyopathy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions, please email: journals.permissions@oup.com.)