High incidence of functional ion-channel abnormalities in a consecutive Long QT cohort with novel missense genetic variants of unknown significance
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High incidence of functional ion-channel abnormalities in a consecutive Long QT cohort with novel missense genetic variants of unknown significance. / Steffensen, Annette Buur; Refaat, Marwan M; David, Jens-Peter; Mujezinovic, Amer; Calloe, Kirstine; Wojciak, Julianne; Nussbaum, Robert L; Scheinman, Melvin M; Schmitt, Nicole.
In: Scientific Reports, Vol. 5, 10009, 12.06.2015, p. 1-13.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - High incidence of functional ion-channel abnormalities in a consecutive Long QT cohort with novel missense genetic variants of unknown significance
AU - Steffensen, Annette Buur
AU - Refaat, Marwan M
AU - David, Jens-Peter
AU - Mujezinovic, Amer
AU - Calloe, Kirstine
AU - Wojciak, Julianne
AU - Nussbaum, Robert L
AU - Scheinman, Melvin M
AU - Schmitt, Nicole
PY - 2015/6/12
Y1 - 2015/6/12
N2 - 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.
AB - 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.
U2 - 10.1038/srep10009
DO - 10.1038/srep10009
M3 - Journal article
C2 - 26066609
VL - 5
SP - 1
EP - 13
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 10009
ER -
ID: 142071484