Compound heterozygosity for mutations Asp611→Tyr in KCNQ1 and Asp609→Gly in KCNH2 associated with severe long QT syndrome

Abstract

LQTS (long QT syndrome) is an inherited cardiac disorder characterized by prolongation of QT interval, torsades de pointes and sudden death. We have identified two heterozygous missense mutations in the KCNQ1 and KCNH2 (also known as HERG) genes [Asp611-->Tyr (D611Y) in KCNQ1 and Asp609-->Gly (D609G) in KCNH2] in a 2-year-old boy with LQTS. The aim of the present study was to characterize the contributions of the mutations in the KCNQ1 and KCNH2 genes relative to the clinical manifestations and electrophysiological properties of LQTS. Six of 11 carriers of D611Y in KCNQ1 had long QT intervals. D609G in KCNH2 was detected only in the proband. Studies on the electrophysiological alterations due to the two missense mutations revealed that the D611Y mutation in KCNQ1 did not show a significant suppression of the currents compared with wild-type, but the time constants of current activation in the mutants were increased compared with that in the wild-type. In contrast, the D609G mutation in KCNH2 showed a dominant-negative suppression. Our results suggest that the mild phenotype produced by the D611Y mutation in KCNQ1 became more serious by addition of the D609G mutation in KCNH2 in the proband.

Long QT syndrome and associated gene mutation carriers in Japanese children: results from ECG screening examinations

“…Mutations in various genes encoding cardiac ion channels and membrane adaptor proteins are known to cause this syndrome [2], and many LQTS mutations have been identified [3][4][5][6]. A previous study [7] has shown that approx.…”

In utero onset of long QT syndrome with atrioventricular block and spontaneous or lidocaine-induced ventricular tachycardia: Compound effects of hERG pore region mutation and SCN5A N-terminus variant

“…Compound mutations account for 4-8 % of the mutations identified in patients with LQTS, but the functional studies had only rarely performed. [10][11][12] The compound mutations may involve the same or different LQTS genes (e.g., two independent KCNQ1 mutations, KCNQ1 + KCNH mutations, KCNQ1 + SCN5A mutations, or rarely hERG + SCN5A mutations). [9][10][11][12] Functional hERG channels develop from the co-assembly of four subunits into a tetrametric protein on the cell membrane.…”

“…6,7 Further diversity appears when an increasing number of compound heterozygote mutations within one or even two different LQTS genes have been reported. [9][10][11][12] Such compound mutations may increase the risk of arrhythmia and are associated with more severe forms of LQTS. But, to date, only limited studies have reported the functional alterations.…”

Genetic modulators of the phenotype in the long QT syndrome: state of the art and clinical impact

“…Additional case reports showed that the clinical manifestations of patients with two concurrent mutations are often characterized by a more severe phenotype [12,13 ]. More recently it has become clear that LQTS patients carrying two or more pathogenic variants either in the same gene (compound heterozygotes) or in different genes (digenic heterozygosity), make up 4-9% of patients [9 ,14].…”