Long Qt Syndrome 6

A number sign (#) is used with this entry because of evidence that long QT syndrome-6 (LQT6) is caused by heterozygous mutation in the KCNE2 gene (603796) on chromosome 21q22.

Digenic inheritance has also been reported; see MOLECULAR GENETICS.

Description

Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (Jongbloed et al., 1999).

For a discussion of genetic heterogeneity of long QT syndrome, see LQT1 (192500).

Clinical Features

Abbott et al. (1999) reported a healthy 38-year-old Caucasian female who had had ventricular fibrillation while jogging. Her resuscitation required defibrillation. The results from echocardiography and cardiac catheterization with electrophysiologic studies and right ventricular biopsy were normal. Subsequent electrocardiograms showed an atypical response to exercise with QTc intervals ranging from 390 to 500 ms.

Molecular Genetics

In 2 healthy females with LQT5, Abbott et al. (1999) identified heterozygosity for different missense mutations in the KCNE2 gene (603796.0002-603796.0003).

In a 76-year-old African American female with acquired long QT syndrome, Abbott et al. (1999) identified a heterozygous missense mutation in the KCNE2 gene (603796.0001).

Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1, 607542; KCNH2, 152427; SCN5A 600163; KCNE1, 176261; and KCNE2) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively).

Digenic Inheritance

Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation.

In a 1-month-old male infant who had syncope, torsade de pointes, cardiac arrest, and a QTc of 460 ms, Millat et al. (2006) identified biallelic digenic mutations: an F60L mutation in the KCNE2 gene (603796.0005) and an R1623Q mutation in the SCN5A gene (600163.0007).