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Sci Rep September 21, 2015; 5 10009.

High incidence of functional ion-channel abnormalities in a consecutive Long QT cohort with novel missense genetic variants of unknown significance.

Steffensen AB , Refaat MM , David JP , Mujezinovic A , Calloe K , Wojciak J , Nussbaum RL , Scheinman MM , Schmitt N .

The Long QT syndrome (LQTS) is a disorder characterized by a prolongation of the QT interval and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. Our objective was to (1) determine the incidence of variants with unknown significance (VUS) in a cohort of consecutive LQTS patients and (2) to determine the percentage of those with novel missense VUS that have demonstrable functional channel abnormalities from a single referral center. We performed genetic screening of candidate genes in 39 probands with a diagnosis of LQTS to identify mutations and variants. Seven variants of unknown significance were identified, six were missense variants and one was a splice site variant. We investigated the six novel missense VUS in five patients; three missense variants in KCNQ1 (L236R, W379R, Y522S) and three missense variants in KCNH2 (R35W, S620G, V491I). We employed two-electrode voltage-clamp experiments in Xenopus laevis oocytes and confocal imaging to characterize the novel missense mutations functionally. We revealed electrophysiological and trafficking loss-of-function phenotypes. This report emphasizes the frequency of adverse channel function in patients with LQTS and the importance of heterologous studies to define channel function.

PubMed ID: 26066609
PMC ID: PMC4464365
Article link: Sci Rep

Genes referenced: actl6a arfgap1 kcne1 kcnh2 kcnq1 mmut
GO keywords: voltage-gated potassium channel activity [+]

Disease Ontology terms: long QT syndrome 1 [+]

Article Images: [+] show captions
References [+] :
Ackerman, Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. 1999, Pubmed

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