Clinical Aspects of Type-1 Long-QT Syndrome by Location, Coding Type, and Biophysical Function of Mutations Involving the KCNQ1 Gene

Abstract

Background-Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded I Ks cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder. Methods and Results-We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (nϭ425), the Netherlands' LQTS Registry (nϭ93), and the Japanese LQTS Registry (nϭ82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (Ͼ50%) or haploinsufficiency (Յ50%) reduction in cardiac repolarizing I Ks potassium channel current.Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; PϽ0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; PϽ0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors. Conclusions-This genotype-phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

“…Conversely, we found a maternal transmission rate of 67% for the dominant negative variants, which are associated with the most severe channel dysfunction, compared with 58% for non-dominant negative variants. 8 Thus, the degree of transmission distortion in LQTS may vary among populations depending on variant type. This may explain the absence of significant female predominance/transmission distortion recently reported in a Norwegian population where most of the identified LQT1 variants led to haploinsufficiency and a moderate channel dysfunction.…”

“…In the heart, KCNQ1 co-assembles with KCNE1, the major cardiac β-subunit, to form the slowly activating K+ channel sensitive to adrenergic regulation. 8,26 In contrast, co-assembly of KCNQ1 with KCNE3 produces a current with nearly instantaneous activation. 27 In colonic crypts, these KCNQ1:KCNE3 channels mediate basolateral K + recycling required for Cl − secretion and their expression is regulated by estrogens.…”

“…8 Asymmetry of parental origin in long QT syndrome H Itoh et al dysfunction, missense variants were categorized according to either a dominant (450% reduction in I Ks current; n = 24) or a non-dominant negative effect (n = 9) on wild-type subunits, according to published heterologous expression studies. Other non-missense variants such as nonsense (n = 6), splice site (n = 7), and frameshift variants (n = 22) with known or assumed loss of function were grouped as haploinsufficiency variants (Supplementary Table S1).…”

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

“…10 In a recent study on 356 LQT1 mutation carriers with known or suspected alterations in the ion-channel function, it was demonstrated that the degree of channel dysfunction in vitro was a major risk factor for cardiac events, independent of clinical risk factors and ␤-blocker therapy. 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.…”

“…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.…”