KCNH2 -K897T Is a Genetic Modifier of Latent Congenital Long-QT Syndrome

Abstract

Background-Clinical heterogeneity among patients with long-QT syndrome (LQTS) sharing the same disease-causing mutation is usually attributed to variable penetrance. One potential explanation for this phenomenon is the coexistence of modifier gene alleles, possibly common single nucleotide polymorphisms, altering arrhythmia susceptibility. We demonstrate this concept in a family segregating a novel, low-penetrant KCNH2 mutation along with a common single nucleotide polymorphism in the same gene. Methods and Results-The proband is a 44-year-old white woman with palpitations associated with presyncope since age 20, who presented with ventricular fibrillation and cardiac arrest. Intermittent QT prolongation was subsequently observed (max QTc, 530 ms), and LQT2 was diagnosed after the identification of a missense KCNH2 mutation (A1116V) altering a conserved residue in the distal carboxyl-terminus of the encoded HERG protein. The proband also carried the common KCNH2 polymorphism K897T on the nonmutant allele. Relatives who carried A1116V without K897T were asymptomatic, but some exhibited transient mild QTc prolongation, suggesting latent disease. Heterologous expression studies performed in cultured mammalian cells and using bicistronic vectors linked to different fluorescent proteins demonstrated that coexpression of A1116V with K897T together resulted in significantly reduced current amplitude as compared with coexpression of either allele with WT-HERG. Thus, the presence of KCNH2-K897T is predicted to exaggerate the I Kr reduction caused by the A1116V mutation. These data explain why symptomatic LQTS occurred only in the proband carrying both alleles. Conclusions-We have provided evidence that a common KCNH2 polymorphism may modify the clinical expression of a latent LQT2 mutation. A similar mechanism may contribute to the risk for sudden death in more prevalent cardiac diseases. (Circulation. 2005;112:1251-1258.)

Epidemiology of Sudden Cardiac Death: Clinical and Research Implications

“…Therefore genes that contribute to sudden cardiac death occurrence have to be separated from genes that lead to associated conditions. Secondly, even for the so-called "monogenic syndromes" such as the long QT syndrome, there may be additional modifier genes that are involved (50,94). For the complex phenotype of overall sudden cardiac death, it is quite likely that for an individual patient, screening may have to be conducted for a panel of genes instead of a single gene.…”

Low Incidence of Sudden Cardiac Death in a Swedish Y111C Type 1 Long-QT syndrome Population

“…The concept of modifier genes, including compound heterozygosity 26 and the addition of single-nucleotide polymorphisms (SNPs) 27,28 to LQTS mutations, has been proposed to explain the phenomenon of phenotypic heterogeneity. 29 Although modifier genes have previously been reported in the context of amplifying the effect of LQTS mutations, 26 -28 a recent study has provided some evidence that SNPs might ameliorate the clinical phenotype of a LQTS mutation.…”

The congenital long QT syndromes from genotype to phenotype: clinical implications

“…Meanwhile, our research group has identified rather serendipitously a first modifier gene for the severity of LQTS [48]. This finding had been preceded by our quantification [49] of the curious phenomenon of 'double' or 'two independent mutations', by which it appears that approximately 5% of LQTS patients inherit two relatively mild mutations by the parents (often asymptomatic) and then manifest severe LQTS, and by the observation by Westenskow et al [50] that two to three individuals from one family carrying one LQTS mutation and the rare single nucleotide polymorphism (SNP) D85N (on KCNE1) had more severe clinical manifestations.…”