Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing

The purpose of this study was to determine the spectrum and prevalence of cardiac channel mutations among a large cohort of consecutive, unrelated patients referred for long QT syndrome (LQTS) genetic testing. Congenital LQTS is a primary cardiac channelopathy. More than 300 mutations have been identified in five genes encoding key ion channel subunits. Until the recent release of the commercial clinical genetic test, LQTS genetic testing had been performed in research laboratories during the past decade. A cardiac channel gene screen for LQTS-causing mutations in KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) was performed for 541 consecutive, unrelated patients (358 females, average age at diagnosis 24 ± 16 years, average QTc 482 ± 57 ms) referred to Mayo Clinic’s Sudden Death Genomics Laboratory for LQTS genetic testing between August 1997 and July 2004. A comprehensive open reading frame and splice site analysis of the 60 protein-encoding exons was conducted using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. Overall, 211 putative pathogenic mutations in KCNQ1 (88), KCNH2 (89), SCN5A (32), KCNE1 (1), and KCNE2 (1) were found in 272 unrelated patients (50%). Among the genotype positive patients (N = 272), 243 had single pathogenic mutations (LQT1: n = 120 patients; LQT2: n = 93; LQT3: n = 26; LQT5: n = 3; LQT6: n = 1), and 29 patients (10% of genotype-positive patients and 5% overall) had two LQTS-causing mutations. The majority of mutations were missense mutations (154/210 [73%]), singletons (identified in only a single unrelated patient: 165/210 [79%]), and novel (125/211 [59%]). None of the mutations identified were seen in more than 1,500 reference alleles. Those patients harboring multiple mutations were younger at diagnosis (15 ± 11 years vs 24 ± 16 years, P =.003). In this comprehensive cardiac channel gene screen of the largest cohort of consecutive, unrelated patients referred for LQTS genetic testing, half of the patients had an identifiable mutation. The majority of mutations continue to represent novel singletons that expand the published compendium of LQTS-causing mutations by 35%. These observations should facilitate diagnostic interpretation of the clinical genetic test for LQTS.