Systematic re-evaluation of ion channel mutations associated with Brugada syndrome

Background: A large number of ion channel variants have been reported to underlie Brugada syndrome (BrS). However, the evidence supporting individual variants is highly heterogeneous.

Objective: We systematically re-evaluated all coding ion channel variants reported in BrS using a modified version of the ACMG-AMP guidelines

Methods: A Pubmed/Medline search was performed to identify all reported BrS ion channel variants. Standardized bioinformatic re-analysis (SIFT, PolyPhen, Mutation Taster, Mutation assessor, FATHMM, GERP, PhyloP, and SiPhy) and re-evaluation of frequency in reference databases (1000 genomes, EVS and ExAC) was performed. The ACMG-AMP guideline-based analysis was modified by stratifying evidence from INa and ICa(L) functional studies into strong (≥90% peak current reduction or ≥50% reduction with significant gating abnormalities) and moderate (50–90% peak current reduction without significant gating abnormalities).

Results: 578 unique coding ion channel variants were identified, the majority of which (79%) were SCN5A variants. 166/456 (36%) SCN5A variants were classified as pathogenic/likely pathogenic. 4/54 (7%) non-SCN5A sodium channel variants were deemed pathogenic/likely pathogenic (SCN10A n=3; SCN1B n=1). 2/39 (5%) calcium channel variants were classified as pathogenic/likely pathogenic (both CACNA1C variants). 2/13 (15%) TRPM4 variants were classified as pathogenic/likely pathogenic. None of the SCN2B, SCN3B, CACNA2D1, CACNB2, HCN4 or potassium channel variants were classified as pathogenic/likely pathogenic. Overall, 66% of reported variants were classified as variants of uncertain significance, while a further 3% were classified as benign/likely benign.

Conclusion: Based on contemporary ACMG-AMP guidelines, only a minority of ion channel variants implicated in BrS fulfil criteria for pathogenicity or likely pathogenicity.