title: Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction.
abstract: 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.
  
  
  
  The purpose of this study was to investigate the clinical and demographic features of SSS patients carrying HCN4 mutations.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.affiliation: Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Cardiology, Ibaraki Children's Hospital, Mito, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Department of Cardiology, Ibaraki Prefectural Central Hospital, Kasama, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Cardiology, Ibaraki Prefectural Central Hospital, Kasama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mishima
authors.affiliation: Department of Pediatrics, Shizuoka Saiseikai General Hospital, Shizuoka, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fukuoka
authors.affiliation: Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kimoto
authors.affiliation: Department of Medicine, Nagasaki University, Nagasaki, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Sakamoto
authors.affiliation: Department of Medicine, Nagasaki University, Nagasaki, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ohkusa
authors.affiliation: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita ,Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aiba
authors.affiliation: Department of Cardiology, Tsukuba University, Tsukuba, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nogami
authors.affiliation: Department of Pediatric Cardiology, Saitama Medical University, Saitama, Japan.
authors.forename: Naokata
authors.initials: N
authors.lastname: Sumitomo
authors.affiliation: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita ,Japan; Division of Cardiology, Nippon Medical School, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.affiliation: Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Koh-Ichiro
authors.initials: KI
authors.lastname: Yoshiura
authors.affiliation: Department of Pediatrics, Tsukuba University, Tsukuba, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Horigome
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.affiliation: Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: makitan@nagasaki-u.ac.jp.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics*; D007223:Infant; D056830:Isolated Noncompaction of the Ventricular Myocardium / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D012804:Sick Sinus Syndrome / Q000235:genetics*; D055815:Young Adult
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
keywords: Atrial fibrillation; HCN4; Left ventricular noncompaction; Mutation; Pacemaker; SCN5A; Sick sinus syndrome