Phenotypic Variability and Unusual Clinical Severity of Congenital Long-QT Syndrome in a Founder Population

Abstract

Background-In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation (A341V). Methods and Results-The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers.When not taking ␤-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (Յ440 ms). A QTc Ͼ500 ms was associated with increased risk for cardiac events (ORϭ4.22; 95% CI, 1.12 to 15.80; Pϭ0.033). We also found that MCs with a heart rate Ͻ73 bpm were at significantly lower risk (ORϭ0.23; 95% CI, 0.06 to 0.86; Pϭ0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7Ϯ4 versus 13Ϯ9 years, both PϽ0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IK s were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions-KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor. (Circulation. 2005;112:2602-2610.)

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

“…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).…”

“…11 However, it has been recently proposed that cellular electrophysiological studies cannot always predict the clinical phenotype of a mutation; despite the severe clinical pheno- type of the A341V mutation carriers, only a mild dominant negative effect was demonstrated in vitro. 7,8 It is evident that clinical observations should modulate the interpretation of experimental findings. It is, however, unclear how the pronounced discrepancy between the in vitro and clinical phenotype in the Y111C population should be interpreted.…”

“…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.…”

Is Symptomatic Long QT Syndrome Associated with Depression in Women and Men?

“…Furthermore, the syndrome exhibits variable expressivity, which means that the type and severity of arrhythmic events (i.e., symptoms) can vary between individuals carrying the same mutation (Brink et al, 2005). While genetic determinants underlying incomplete penetrance and variable expressivity remain unclear (Giudicessi & Ackerman, 2013a), some demographic factors, for instance, male sex in younger patients and female sex in adult patients, have been suggested to be associated with the arrhythmic risk in LQTS (Locati et al, 1998).…”

A Refined Multiscale Self-Entropy Approach for the Assessment of Cardiac Control Complexity: Application to Long QT Syndrome Type 1 Patients

“…RMSCE and RMSsE were evaluated over heart period (HP) and QT interval series derived from 24-hour Holter electrocardiographic recordings in a long QT syndrome type 1 (LQT1) founder population featuring the KCNQ1-A341V mutation. LQT1 mutation carriers (MCs) were subdivided into asymptomatic MCs (AMCs) and symptomatic MCs (SMCs) based on the severity of the symptoms and different arrhythmic risk, and contrasted to non MCs (NMCs) belonging to the same family line [18,19].…”