Taisuke Ishikawa1, Seiko Ohno2, Takashi Murakami3, Kentaro Yoshida4, Hiroyuki Mishima4, Tetsuya Fukuoka5, Hiroki Kimoto1, Risa Sakamoto6, Takafumi Ohkusa6, Takeshi Aiba7, Akihiko Nogami8, Naokata Sumitomo9, Wataru Shimizu10, Koh-Ichiro Yoshiura11, Hitoshi Horigome12, Minoru Horie2, Naomasa Makita13. 1. Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 2. Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan. 3. Department of Cardiology, Ibaraki Children's Hospital, Mito, Japan. 4. Department of Cardiology, Ibaraki Prefectural Central Hospital, Kasama, Japan. 5. Department of Pediatrics, Shizuoka Saiseikai General Hospital, Shizuoka, Japan. 6. Department of Medicine, Nagasaki University, Nagasaki, Japan. 7. Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita ,Japan. 8. Department of Cardiology, Tsukuba University, Tsukuba, Japan. 9. Department of Pediatric Cardiology, Saitama Medical University, Saitama, Japan. 10. Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita ,Japan; Division of Cardiology, Nippon Medical School, Tokyo, Japan. 11. Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 12. Department of Pediatrics, Tsukuba University, Tsukuba, Japan. 13. Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: makitan@nagasaki-u.ac.jp.
Abstract
BACKGROUND: Familial sick sinus syndrome (SSS) is often attributable to mutations in genes encoding the cardiac Na channel SCN5A and pacemaker channel HCN4. We previously found that SSS with SCN5A mutations shows early onset of manifestations and male predominance. Despite recent reports on the complications of atrial fibrillation (AF) and left ventricular noncompaction (LVNC) in patients with SSS caused by HCN4 mutations, their overall clinical spectrum remains unknown. OBJECTIVE: The purpose of this study was to investigate the clinical and demographic features of SSS patients carrying HCN4 mutations. METHODS: We genetically screened 38 unrelated SSS families and functionally analyzed the mutant SCN5A and HCN4 channels by patch clamping. We also evaluated the clinical features of familial SSS by a meta-analysis of 48 SSS probands with mutations in HCN4 (n = 16) and SCN5A (n = 32), including previously reported cases, and 538 sporadic SSS cases. RESULTS: We identified two HCN4 and three SCN5A loss-of-function mutations in our familial SSS cohort. Meta-analysis of HCN4 mutation carriers showed a significantly younger age at diagnosis (39.1 ± 21.7 years) than in sporadic SSS (74.3 ± 0.4 years; P <.001), but a significantly older age than in SCN5A mutation carriers (20.0 ± 17.6 years; P = .003). Moreover, HCN4 mutation carriers were more frequently associated with AF (43.8%) and LVNC (50%) and with older age at pacemaker implantation (43.5 ± 22.1 years) than were SCN5A mutation carriers (17.8 ± 16.5 years; P <.001). CONCLUSION: SSS with HCN4 mutations may form a distinct SSS subgroup characterized by early clinical manifestation after adolescence and frequent association with AF and LVNC.
BACKGROUND:Familial sick sinus syndrome (SSS) is often attributable to mutations in genes encoding the cardiac Na channel SCN5A and pacemaker channel HCN4. We previously found that SSS with SCN5A mutations shows early onset of manifestations and male predominance. Despite recent reports on the complications of atrial fibrillation (AF) and left ventricular noncompaction (LVNC) in patients with SSS caused by HCN4 mutations, their overall clinical spectrum remains unknown. OBJECTIVE: The purpose of this study was to investigate the clinical and demographic features of SSS patients carrying HCN4 mutations. METHODS: We genetically screened 38 unrelated SSS families and functionally analyzed the mutant SCN5A and HCN4 channels by patch clamping. We also evaluated the clinical features of familial SSS by a meta-analysis of 48 SSS probands with mutations in HCN4 (n = 16) and SCN5A (n = 32), including previously reported cases, and 538 sporadic SSS cases. RESULTS: We identified two HCN4 and three SCN5A loss-of-function mutations in our familial SSS cohort. Meta-analysis of HCN4 mutation carriers showed a significantly younger age at diagnosis (39.1 ± 21.7 years) than in sporadic SSS (74.3 ± 0.4 years; P <.001), but a significantly older age than in SCN5A mutation carriers (20.0 ± 17.6 years; P = .003). Moreover, HCN4 mutation carriers were more frequently associated with AF (43.8%) and LVNC (50%) and with older age at pacemaker implantation (43.5 ± 22.1 years) than were SCN5A mutation carriers (17.8 ± 16.5 years; P <.001). CONCLUSION: SSS with HCN4 mutations may form a distinct SSS subgroup characterized by early clinical manifestation after adolescence and frequent association with AF and LVNC.
Authors: Rosa B Thorolfsdottir; Gardar Sveinbjornsson; Hildur M Aegisdottir; Stefania Benonisdottir; Lilja Stefansdottir; Erna V Ivarsdottir; Gisli H Halldorsson; Jon K Sigurdsson; Christian Torp-Pedersen; Peter E Weeke; Søren Brunak; David Westergaard; Ole B Pedersen; Erik Sorensen; Kaspar R Nielsen; Kristoffer S Burgdorf; Karina Banasik; Ben Brumpton; Wei Zhou; Asmundur Oddsson; Vinicius Tragante; Kristjan E Hjorleifsson; Olafur B Davidsson; Sridharan Rajamani; Stefan Jonsson; Bjarni Torfason; Atli S Valgardsson; Gudmundur Thorgeirsson; Michael L Frigge; Gudmar Thorleifsson; Gudmundur L Norddahl; Anna Helgadottir; Solveig Gretarsdottir; Patrick Sulem; Ingileif Jonsdottir; Cristen J Willer; Kristian Hveem; Henning Bundgaard; Henrik Ullum; David O Arnar; Unnur Thorsteinsdottir; Daniel F Gudbjartsson; Hilma Holm; Kari Stefansson Journal: Eur Heart J Date: 2021-05-21 Impact factor: 29.983
Authors: Michael J Wallace; Mona El Refaey; Pietro Mesirca; Thomas J Hund; Matteo E Mangoni; Peter J Mohler Journal: Front Genet Date: 2021-04-01 Impact factor: 4.599