Keisuke Abe1, Taku Machida1, Naokata Sumitomo1, Hirokazu Yamamoto1, Kimie Ohkubo1, Ichiro Watanabe1, Takeru Makiyama1, Satoki Fukae1, Masaki Kohno1, Daniel T Harrell1, Taisuke Ishikawa1, Yukiomi Tsuji1, Akihiko Nogami1, Taichi Watabe1, Yasushi Oginosawa1, Haruhiko Abe1, Koji Maemura1, Hideki Motomura1, Naomasa Makita2. 1. From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan. 2. From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan. makitan@nagasaki-u.ac.jp.
Abstract
BACKGROUND: Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identification of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. METHODS AND RESULTS: We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identified 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was significantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P<0.001) or nonfamilial SSS (74.3±0.4 years; n=538; P<0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years). CONCLUSIONS: The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations.
BACKGROUND:Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identification of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. METHODS AND RESULTS: We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identified 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was significantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P<0.001) or nonfamilial SSS (74.3±0.4 years; n=538; P<0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years). CONCLUSIONS: The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations.
Authors: Ana Morales; Daniel D Kinnamon; Elizabeth Jordan; Julia Platt; Matteo Vatta; Michael O Dorschner; Carl A Starkey; Jonathan O Mead; Tomohiko Ai; Wylie Burke; Julie Gastier-Foster; Gail P Jarvik; Heidi L Rehm; Deborah A Nickerson; Ray E Hershberger Journal: Circ Genom Precis Med Date: 2020-03-11
Authors: Karolina Sanner; Johanna Mueller-Leisse; Christos Zormpas; David Duncker; Andreas Leffler; Christian Veltmann Journal: Cardiology Date: 2021-07-08 Impact factor: 1.869