Long Qt Syndrome 13

A number sign (#) is used with this entry because of evidence that long QT syndrome-13 (LQT13) is caused by heterozygous mutation in the KCNJ5 gene (600734) on chromosome 11q24.

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

Yang et al. (2010) studied a large 4-generation Chinese family segregating autosomal dominant long QT syndrome (LQTS). The proband was a 62-year-old woman who had a 40-year history of syncopal episodes. Comprehensive clinical evaluation included an echocardiogram that showed no structural or functional cardiac abnormalities, but an electrocardiogram (ECG) that revealed a markedly prolonged QT interval (corrected QT = 520 ms). Subsequent evaluation of 49 family members identified 9 patients with LQTS characterized by similar clinical features. The proband developed persistent atrial fibrillation, which was also observed in 3 affected relatives. The proband had a younger brother who had a series of seizures and syncopal episodes after birth and died suddenly at 7 days of life.

Wang et al. (2013) reexamined 9 mutation-positive members of the large 4-generation Han Chinese family originally reported by Yang et al. (2010). Recurrent syncope was present in 5 patients, and 3 had symptoms of heart failure, believed to be secondary to coronary artery disease, atrioventricular block, and pulmonary embolism, respectively. Seven patients had hypertension, and 3 had atrial fibrillation and/or atrial tachycardia. Wang et al. (2013) noted that mutation-related primary aldosteronism was excluded based on negative results of aldosterone/renin ratio and 24-hour urine aldosterone tests.

Clinical Variability

Kokunai et al. (2014) reported a 35-year-old man who developed periodic muscle paralysis associated with reduced serum potassium concentrations beginning at age 31 years. He had no cardiac symptoms, but EKG showed possible sinus arrest during the attacks and prominent U waves at normal potassium concentrations. Although Kokunai et al. (2014) suggested that the phenotype resembled Andersen-Tawil syndrome (LQT7; 170390), the patient did not have dysmorphic features. There was a strong family history of significant cardiac arrhythmia, but neither detailed clinical features nor DNA from family members was available.

Mapping

In a large, 4-generation Chinese family segregating autosomal dominant long QT syndrome, in which affected individuals were negative for mutation in 12 known LQTS genes, Yang et al. (2010) performed genomewide linkage analysis and obtained a maximum lod score of 5.12 (theta = 0.00) at D11S4123 on chromosome 11q24.3. Haplotype analysis of family members revealed a 4.78-cM shared region on 11q23.3-q23.4, flanked by markers D11S4151 and D11S4123 and containing 15 defined genes.

Molecular Genetics

In a large, 4-generation Chinese family with autosomal dominant long QT syndrome mapping to chromosome 11q23.3-q23.4, Yang et al. (2010) sequenced the candidate gene KCNJ5 and identified heterozygosity for a missense mutation (G387R; 600734.0001) in affected individuals. The mutation, which was not found in 528 ethnically matched controls, was also detected in 2 asymptomatic family members, indicating incomplete penetrance and a need for long-term monitoring of carriers.

Kokunai et al. (2014) identified heterozygosity for the G387R mutation in the KCNJ5 gene in a 35-year-old man with hypokalemic periodic paralysis and prominent U waves. The mutation was found by exome capture resequencing analysis of 162 genes encoding ion channels. In vitro functional expression studies in Xenopus oocytes showed that coexpression of KCNJ2 (600681) with mutant KCNJ5 significantly reduced the inwardly rectifying potassium current compared to that observed with coexpression of KCNJ2 with wildtype KCNJ5. Kokunai et al. (2014) concluded that the reduction in this current caused by loss of function of KCNJ2 is the underlying cause of periodic paralysis and cardiac conduction abnormalities in this patient.