Clinical data collection

Clinical records from antemortem BrS cases (n = 6) and where SADS families had undergone evaluation at St George’s Hospital London were retrospectively reviewed before study inclusion. Inclusion criteria for SADS cases were as follows: a witnessed sudden death within 1 hour of symptoms, or last seen alive within 12 hours of death; aged 1-64 years; no prior recorded cardiac disease; no history of epilepsy; a normal full coroner’s post mortem; negative toxicology; and a normal expert cardiac pathologists’ examination (12). In total, families of 61 SADS probands with retained cardiac tissue underwent clinical evaluation at St George’s Hospital. This included assessment with 12-lead, signal-averaged, and exercise ECGs; echocardiography; and ambulatory cardiac monitoring. Among families without diagnostic features of an inherited cardiac condition, an ajmaline provocation challenge was performed according to an established protocol (13). Cases with a diagnosis of familial BrS were included in the presence of a spontaneous or drug-induced type 1 Brugada ECG pattern in the standard or high precordial leads in at least 1 first-degree relative. Antemortem BrS and familial BrS were diagnosed based on expert consensus criteria (2). Electrocardiogram criteria for a type 1 Brugada ECG pattern consisted of ST-segment elevation with coved morphology ≥2 mm in ≥1 lead among the right precordial leads.

Demographics and clinical data for SCD and control cohorts was obtained following review of the CRY-CCP database. The consensus-derived Shanghai score was calculated for each decedent with an antemortem diagnosis of BrS, and for familial BrS cases, the relative with the highest score following a diagnosis of BrS (1). SADS cases without familial evaluation data but with pathogenic or likely pathogenic SCN5A loss of function variants (as per American College of Medical Genetics and Genomics [ACMG] criteria [14]) were identified from the same base cohort. Noncardiac deaths were determined by information from the referring pathologist’s autopsy and final coronial judgment.