A Single Na ⁺ Channel Mutation Causing Both Long-QT and Brugada Syndromes

TLDR

Mutations in SCN5A, the gene encoding the cardiac Na⁺ channel, have been identified in two distinct sudden‑death syndromes: long‑QT syndrome (LQT3) and Brugada syndrome. The authors screened SCN5A in an 8‑generation kindred with nocturnal sudden death, QT prolongation, and Brugada ECG, and performed ECGs on 79 adults with known carrier status. An insertion of 3 nucleotides (TGA) at position 5537 (1795insD) was found in all affected family members, associated with prolonged PR, QRS, and QT intervals, right‑precordial ST elevation, 25 sudden deaths (16 nocturnal), and functional studies showing shifts in activation/inactivation that reduce Na⁺ current, indicating that LQT3 and Brugada syndrome are allelic disorders sharing a common genotype.

Abstract

Mutations in SCN5A, the gene encoding the cardiac Na(+) channel, have been identified in 2 distinct diseases associated with sudden death: one form of the long-QT syndrome (LQT(3)) and the Brugada syndrome. We have screened SCN5A in a large 8-generation kindred characterized by a high incidence of nocturnal sudden death, and QT-interval prolongation and the "Brugada ECG" occurring in the same subjects. An insertion of 3 nucleotides (TGA) at position 5537, predicted to cause an insertion of aspartic acid (1795insD) in the C-terminal domain of the protein, was linked to the phenotype and was identified in all electrocardiographically affected family members. ECGs were obtained from 79 adults with a defined genetic status (carriers, n=43; noncarriers, n=36). In affected individuals, PR and QRS durations and QT intervals are prolonged (P<0.0001 for all parameters). ST segment elevation in the right precordial leads is present as well (P<0.0001). Twenty-five family members died suddenly, 16 of them during the night. Expression of wild-type and mutant Na(+) channels in Xenopus oocytes revealed that the 1795insD mutation gives rise to a 7.3-mV negative shift of the steady-state inactivation curve and an 8.1-mV positive shift of the steady-state activation curve. The functional consequence of both shifts is likely to be a reduced Na(+) current during the upstroke of the action potential. LQT(3) and Brugada syndrome are allelic disorders but may also share a common genotype.