The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds

Abstract

Background-The impressive clinical heterogeneity of the long-QT syndrome (LQTS) remains partially unexplained. In a South African (SA) founder population, we identified a common LQTS type 1 (LQT1)-causing mutation (KCNQ1-A341V) associated with high clinical severity. We tested whether the arrhythmic risk was caused directly by A341V or by its presence in the specific ethnic setting of the SA families. Methods and Results-Seventy-eight patients, all with a single KCNQ1-A341V mutation, from 21 families and 8 countries were compared with 166 SA patients with A341V and with 205 non-A341V LQT1 patients. In the 2 A341V populations (SA and non-SA), the probability of a first event through 40 years of age was similar (76% and 82%), and the QTc was 484Ϯ42 versus 485Ϯ45 ms (PϭNS). Compared with the 205 non-A341V patients with the same median follow-up (30 versus 32 years), the 244 A341V patients were more likely to have cardiac events (75% versus 24%), were younger at first event (6 versus 11 years), and had a longer QTc (485Ϯ43 versus 465Ϯ38 ms) (all PϽ0.001). Arrhythmic risk remained higher (PϽ0.0001) even when the A341V patients were compared with non-A341V patients with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. A341V patients had more events despite ␤-blocker therapy. Conclusions-The hot spot KCNQ1-A341V predicts high clinical severity independently of the ethnic origin of the families. This higher risk of cardiac events also persists when compared with LQT1 patients with either transmembrane or dominant-negative mutations. The identification of this high-risk mutation and possibly others may improve the risk stratification and management of LQTS.

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

“…1,18 The absolute majority (86%) of the Y111C mutation carriers exhibits phenotypic effects of the mutation in the form of a prolonged QTc, which usually corresponds to an increased risk of developing symptoms. The electrocardiographic finding of a markedly prolonged mean QTc in the Y111C population is comparable with that of the A341V population 8 ; however, when comparing characteristics related to the concept of clinical severity, such as proportion of symptomatic mutation carriers (30% versus 75%, PϽ0.001), median age at onset (11 versus 6 years, PϽ0.001), incidence of ACA (1.25% versus 30%, PϽ0.001), and SCD (0% versus 13.5%), the differences between the 2 populations are convincing.…”

“…1 Clinical data on the Y111C mutation carriers was compared with the published data on 244 A341V-KCNQ1 mutation carriers and 205 LQT1/non-A341V mutation carriers. 8 Infant death rates and overall death rates derived from the historical data were compared with demographic data on age-stratified mortality rates in the Swedish population. 14 …”

“…To examine the apparent benign phenotype of the Swedish Y111C mutation carriers (nϭ80), the clinical presentation was compared with the published data on the carriers of the A341V mutation 7,8 (nϭ244), a dominant-negative KCNQ1 mutation associated with a severe phenotype (Table 2), and a genetically heterogeneous LQT1 population 8 (nϭ205), not including any A341V families (Table 3).…”

“…High-risk mutations have been identified within the LQT1 subgroup. [7][8][9][10][11] The Y111C-KCNQ1 (c.332AϾG) mutation has previously been described in 1 patient, a 36-year-old woman, who presented with syncope at the age of 3 years. 3 She experienced Ͼ30 syncopal episodes triggered by emotional or physical stress and had a QT interval, corrected for heart rate, of 520 ms. Electrophysiological studies subsequently demonstrated that the Y111C mutation causes intracellular sequestration of mutated ion channels in the endoplasmic reticulum that renders them inactive.…”

Recurrent and founder mutations in inherited cardiac diseases in the Netherlands

“…Dutch founder mutations can be identified in North America and South Africa in particular. 8,9 Thirdly, despite the relatively small size of the country, interesting differences within the Netherlands are recognised which originate mainly from geographic and religious isolation. Geographically, major rivers divided the North from the South, the Zuiderzee isolated people living on islands and peninsulas in the north-western parts of the Netherlands and the absence of developed transport systems resulted in endogamy of more isolated rural areas (i.e.…”