Spectrum of mutations in long-QT syndrome genes KVLQT1, HERG, SCN5A, KCNE1, and KCNE2

Background-Long-QT Syndrome (LQTS) is a cardiovascular disorder characteriz ed by prolongation of the QT interval on ECG and presence of syncope, seizu res, and sudden death. Five genes have been implicated in Romano-Ward syndr ome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and K CNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielse n syndrome, a form of LQTS associated with deafness, a phenotypic abnormali ty inherited in an autosomal recessive fashion. Methods and Results-We used mutational analyses to screen a pool of 262 unr elated individuals with LQTS for mutations in the 5 defined genes. We ident ified 134 mutations in addition to the 43 that we previously reported. Eigh ty of the mutations were novel. The total number of mutations in this popul ation is now 177 (68% of individuals). Conclusions KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mut ations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift muta tions (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembra ne (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individu al.