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Background-The electrocardiographic short QT-interval syndrome forms a distinct clinical entity presenting with a high rate of sudden death and exceptionally short QT intervals. The disorder has recently been linked to gain-of-function mutation in KCNH2. The present study demonstrates that this disorder is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene. Methods and Results-A 70-year man presented with idiopathic ventricular fibrillation. Both immediately after the episode and much later, his QT interval was abnormally short without any other physical or electrophysiological anomalies. Analysis of candidate genes identified a g919c substitution in KCNQ1 encoding the K ϩ channel KvLQT1. Functional studies of the KvLQT1 V307L mutant (alone or coexpressed with the wild-type channel, in the presence of IsK) revealed a pronounced shift of the half-activation potential and an acceleration of the activation kinetics leading to a gain of function in I Ks . When introduced in a human action potential computer model, the modified biophysical parameters predicted repolarization shortening. Conclusions-We present an alternative molecular mechanism for the short QT-interval syndrome. Functional and computational studies of the KCNQ1 V307L mutation identified in a patient with this disorder favor the association of short QT with mutation in KCNQ1. Key Words: death, sudden Ⅲ genetics Ⅲ arrhythmia Ⅲ ion channels Ⅲ fibrillation, ventricular I n recent years, extensive progress has been made in unraveling the pathophysiology of the monogenic arrhythmia syndromes among which are long-QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. 1 The latest addition to this class of disorders is the description of families with a high rate of sudden death and exceptionally short QT intervals, 2 recently attributed to gain-of-function mutation in KCNH2. 3 In this study, we demonstrate that this disorder is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene that encodes the KvLQT1 K ϩ channel, which, in association with the ␤-subunit IsK, forms the slow component of the cardiac delayed rectifier K ϩ current (I Ks ). 4 Methods Patient CharacteristicsA 70-year-old man was successfully resuscitated after a ventricular fibrillation episode. He had been without complaints up until then, and his family history was unremarkable. Physical examination revealed no abnormalities. His ECG is presented in Figure 1. Sinus rhythm was present with normal conduction intervals and a QT interval of 290 ms (QTc, 302 ms). Similarly short QT intervals were observed on every ECG up to 3 years of follow-up. Biochemical analysis at the time of admission, including echocardiography, exercise testing, coronary angiography, left (LV) and right ventricular (RV) angiography, scintigraphy, and ergonovine coronary spasm test, revealed no abnormalities. Nuclear LV ejection fraction was 49%. During electrophysiological study, no arrhythmias could be induced. The electrophysiology ...

Objective To determine the spectrum and prevalence of mutations in the RYR2-encoded the cardiac ryanodine receptor in cases with exertional syncope and normal QTc. Background Mutations in the RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by < 40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts. Methods Mutational analysis of all RYR2 exons was performed using PCR, DHPLC, and DNA sequencing on 155 unrelated patients (49% females, 96% white, age at diagnosis 20 ± 15 years, mean QTc 428 ± 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome (LQTS) but with QTc < 480 ms and a subsequent negative LQTS genetic test (n = 45). Results Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two thirds of the CPVT1-positive patients had mutations that localized to one of 16 exons. Conclusions Possible CPVT1 mutations in RYR2 were identified in nearly half of this cohort. 45 of the 105 translated exons are now known to host possible mutations. Considering that ~65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.

Patients with Beckwith-Wiedemann syndrome (BWS) have an increased risk to develop cancer in childhood, especially Wilms tumor and hepatoblastoma. The risk varies depending on the cause of BWS. We obtained clinical and molecular data in our cohort of children with BWS, including tumor occurrences, and correlated phenotype and genotype. We obtained similar data from larger cohorts reported in the literature. Phenotype, genotype and tumor occurrence were available in 229 of our own patients. Minor differences in phenotype existed depending on genotype/epigenotype, similar to earlier studies. By adding patients from the literature, we obtained data on genotype and tumor occurrence of in total 1,971 BWS patients. Tumor risks were highest in the IC1 (H19/IGF2:IG-DMR) hypermethylation subgroup (28%) and pUPD subgroup (16%) and were lower in the KCNQ1OT1:TSS-DMR (IC2) subgroup (2.6%), CDKN1C (6.9%) subgroup, and the group in whom no molecular defect was detectable (6.7%). Wilms tumors (median age 24 months) were frequent in the IC1 (24%) and pUPD (7.9%) subgroups. Hepatoblastoma occurred mostly in the pUPD (3.5%) and IC2 (0.7%) subgroups, never in the IC1 and CDKN1C subgroups, and always before 30 months of age. In the CDKN1C subgroup 2.8% of patients developed neuroblastoma. We conclude tumor risks in BWS differ markedly depending on molecular background. We propose a differentiated surveillance protocol, based on tumor risks in the various molecular subgroups causing BWS. © 2016 Wiley Periodicals, Inc.