Spectrum of Mutations in Long-QT Syndrome Genes

TLDR

Long‑QT Syndrome is a cardiovascular disorder marked by prolonged QT interval, syncope, seizures, and sudden death, with five genes (KVLQT1, HERG, SCN5A, KCNE1, KCNE2) implicated in the autosomal dominant Romano‑Ward form and mutations in KVLQT1 and KCNE1 also causing the recessive Jervell and Lange‑Nielsen syndrome with deafness. The study performed mutational analyses on 262 unrelated LQTS patients to screen for mutations in the five known genes. The analysis uncovered 177 distinct mutations (68% of the cohort), with KVLQT1 and HERG accounting for 87% of cases, missense mutations predominating (72%), and most variants localized to intracellular (52%) or transmembrane (30%) domains, while 78% were unique to a single family or individual.

Abstract

Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion.We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals).KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (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 individual.