Molecular Basis of the Long QT Syndrome Associated With Deafness

ABSTRACT & COMMENTARY

Synopsis: The Jervell and Lange-Nielson and a subgroup of the Romano-Ward syndrome are closely linked.

Source: Splawski I, et al. N Engl J Med 1997;336: 1562-1567.

The jervell and lange-nielsen syndrome is a congenital disease characterized by highly symptomatic patients with long QTc intervals and deafness and an autosomal recessive pattern of inheritance. The Romano-Ward syndrome also results in a long QTc interval, but it has an autosomal dominant pattern of inheritance. In this paper, Splawski and colleagues describe the genetic relationship between these two conditions.

Splawski et al describe a family of Scottish descent into which an infant was born with the Jervell and Lange-Nielson syndrome. The parents were second cousins. The infant had bradycardia, a long QTc interval, and deafness. When the infant was 7 months old, her mother died suddenly from a cardiac arrest. Subsequent evaluation revealed that 14 family members had clearly abnormal QTc intervals (0.47-0.53), and 32 additional members had borderline QTc prolongation. Six members had a history of syncope. No other family members were deaf. Both parents of the affected infant were found to be heterozygotes for a long QT syndrome, suggesting that the infant carried two copies of the abnormal gene. Analysis of the pattern of the QTc prolongation inheritance confirmed that it was autosomal dominant. Linkage analyses suggested that the genetic defect was in the KVLQT1 gene on chromosome 11, a gene known to join with another protein (minK) to form cardiac Iks potassium channels. Both KVLQT1 and minK are also expressed in the inner ear, and defects in minK have been associated with deafness in some animal species. Splawski et al conclude that the Jervell and Lange-Nielsen and a subgroup of the Romano-Ward syndromes are closely linked. The former is the result of two abnormal KVLQT1 genes, while the latter is produced by the presence of one normal and one abnormal gene.

COMMENT BY JOHN P. DiMARCO, MD, PhD

The long QT syndrome has been the subject of intense study by molecular geneticists over the last decade. There are now four identified chromosomal abnormalities that are associated with this syndrome, and others are likely to be discovered. All these genotypes share the clinical finding of prolonged cardiac repolarization, with a tendency for syncope and cardiac arrest. Subtle clinical characteristics that may differentiate the syndromes are likely to be identified once more families have been fully studied.

The Jervell and Lange-Nielsen and the Romano-Ward syndromes were the first two congenital long QT syndromes to be clinically described. This paper explains the relationship between these two conditions. The original description of the Romano-Ward syndrome required only a long QTc interval and a tendency toward ventricular arrhythmias. There are now several described genetic abnormalities that can result in this phenotype involving both defects in potassium and sodium channel function. As shown in this paper, one of the subsets of Romano-Ward syndrome involves a gene which, when present in a homozygous pattern, results in more marked abnormalities in both repolarization and deafness, the clinical pattern described by Jervell and Lange-Nielsen.

The paper is an excellent example of how molecular genetics is revamping the way we understand clinical syndromes. The next step will be to try and direct therapy at specific, genetically determined targets.