BACKGROUND-Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.

BACKGROUND Long QT syndrome (LQTS) is a potentially lethal, highly treatable cardiac channelopathy for which genetic testing has matured from discovery to translation and now clinical implementation. OBJECTIVES Here we examine the spectrum and prevalence of mutations found in the first 2,500 unrelated cases referred for the FAMILION® LQTS clinical genetic test. METHODS Retrospective analysis of the first 2,500 cases (1,515 female patients, average age at testing 23 ± 17 years, range 0 to 90 years) scanned for mutations in 5 of the LQTS-susceptibility genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). RESULTS Overall, 903 referral cases (36%) hosted a possible LQTS-causing mutation that was absent in >2,600 reference alleles; 821 (91%) of the mutation-positive cases had single genotypes, whereas the remaining 82 patients (9%) had >1 mutation in ≥1 gene, including 52 cases that were compound heterozygous with mutations in >1 gene. Of the 562 distinct mutations, 394 (70%) were missense, 428 (76%) were seen once, and 336 (60%) are novel, including 92 of 199 in KCNQ1, 159 of 226 in KCNH2, and 70 of 110 in SCN5A. CONCLUSION This cohort increases the publicly available compendium of putative LQTS-associated mutations by >50%, and approximately one-third of the most recently detected mutations continue to be novel. Although control population data suggest that the great majority of these mutations are pathogenic, expert interpretation of genetic test results will remain critical for effective clinical use of LQTS genetic test results.

This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation.

Brugada syndrome patients with mutations exhibit more conduction abnormalities on ECG and have higher risk for cardiac events.