Long Qt Syndrome 9

A number sign (#) is used with this entry because long QT syndrome-9 (LQT9) is caused by heterozygous mutation in the CAV3 gene (601253), which encodes caveolin-3, on chromosome 3p25.

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).

Molecular Genetics

Vatta et al. (2006) analyzed the CAV3 gene (601253) in 905 unrelated patients with long QT syndrome who had previously been tested for mutations in known LQT genes; in 6 patients, they identified 4 heterozygous missense mutations (601253.0016-601253.0019, respectively) that were not found in more than 1,000 control alleles. Functional studies showed that the mutant caveolin-3 resulted in a 2- to 3-fold increase in the late sodium current of the cardiac sodium channel compared with wildtype.

Cronk et al. (2007) analyzed the CAV3 gene in necropsy tissue from 134 unrelated cases of sudden infant death syndrome (SIDS; 272120) and identified 3 missense mutations in 3 of 50 black infants (601253.0018; 601253.0020; 601253.0021). No mutations were detected in 1 Hispanic or 83 Caucasian infants. Voltage clamp studies demonstrated a gain-of-function phenotype for all 3 CAV3 mutations, with a 5-fold increase in late sodium current compared to controls.

Digenic Inheritance

Vatta et al. (2006) identified a long QT syndrome patient who had biallelic digenic mutations: a 14-year-old girl with nonexertional syncope and a 'seizure-like' presentation, who had U waves, sinus bradycardia, and a QTc of 405 ms on ECG, was found to carry a missense mutation in the LQT2-associated KCNH2 gene as well as a mutation in the CAV3 gene (see 601253.0018 and 152427.0024).