Mutations in MYBPC3 and MYH7 in Association with Brugada Type 1 ECG Pattern: Overlap between Brugada Syndrome and Hypertrophic Cardiomyopathy?

Abstract

Brugada syndrome (BrS) is an inherited disorder with high allelic and genetic heterogeneity clinically characterized by typical coved-type ST segment elevation at the electrocardiogram (ECG), which may occur either spontaneously or after provocative drug testing. BrS is classically described as an arrhythmic condition occurring in a structurally normal heart and is associated with the risk of ventricular fibrillation and sudden cardiac death (SCD). We studied five patients with spontaneous or drug-induced type 1 ECG pattern, variably associated with symptoms and a positive family history through a Next Generation Sequencing panels approach, which includes genes of both channelopathies and cardiomyopathies. We identified variants in MYBPC3 and in MYH7, hypertrophic cardiomyopathy (HCM) genes (MYBPC3: p.Lys1065Glnfs*12 and c.1458-1G > A, MYH7: p.Arg783His, p.Val1213Met, p.Lys744Thr). Our data propose that Brugada type 1 ECG may be an early electrocardiographic marker of a concealed structural heart disease, possibly enlarging the genotypic overlap between Brugada syndrome and cardiomyopathies.

Diagnostic yield and variant reassessment in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome

“…But cardiac hypertrophy seems to be exclusively rare phenomenon in patients with channelopathies. We performed search through the current literature and found two clinical case reports of HCM patients: one with rare variant (p.Asp872Asn, VUS) in the SCN5A gene (no arrhythmic phenotype mentioned) ( Cronin et al, 2018 ), and second patient with Brugada pattern on ECG and two rare variants in the MYH7 and MyBPC3 genes ( Farnè et al, 2021 ). Whether BrS and HCM may have a common pathogenic mechanism remain unsolved.…”

Brugada Syndrome: More than a Monogenic Channelopathy

“…In particular, an increase in epicardial collagen, fibrosis and fatty infiltration, a reduction in connexin43 expression and altered gap junction communication, particularly in the RVOT, were detected [ 12 , 89 , 107 ]. These alterations are typically associated with cardiomyopathies, and an overlap in clinical as well as molecular features between BrS, arrhythmogenic cardiomyopathy (ACM/ARVC), hypertrophic cardiomyopathy, and laminopathies are emerging [ 108 , 109 , 110 ]. As in dilated cardiomyopathies, RVOT dilation reduced RV ejection fraction and RV wall motion impairment, in addition to age-related fibrosclerotic degeneration in the RV myocardium, which can also take place in BrS over decades [ 103 , 111 ].…”