title: HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.
abstract: BACKGROUND
  Familial forms of primary sinus bradycardia have sometimes been attributed to mutations in HCN4, SCN5A, and ANK2. In these studies, no structural cardiac alterations were reported in mutation carriers. However, a cluster of reports in the literature describe patients presenting with sinus bradycardia in association with left ventricular noncompaction cardiomyopathy (LVNC), pointing to a shared genetic cause.
  
  
  OBJECTIVE
  This study sought to identify the genetic defect underlying the combined clinical presentation of bradycardia and LVNC, hypothesizing that these 2 clinical abnormalities have a common genetic cause.
  
  
  METHODS
  Exome sequencing was carried out in 2 cousins from the index family that were affected by the combined bradycardia-LVNC phenotype; shared variants thus identified were subsequently overlaid with the chromosomal regions shared among 5 affected family members that were identified using single nucleotide polymorphism array analysis.
  
  
  RESULTS
  The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the 2 affected cousins. One of these, p.Gly482Arg in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in 3 additional families with the same clinical combination of bradycardia and LVNC identified HCN4 mutations in each. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage dependence of activation, consistent with the observed bradycardia.
  
  
  CONCLUSIONS
  Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardium.
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Milano
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Alexa M C
authors.initials: AM
authors.lastname: Vermeer
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Lodder
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands; ICIN-Netherlands Heart Institute, Utrecht, the Netherlands.
authors.forename: Julien
authors.initials: J
authors.lastname: Barc
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Alex V
authors.initials: AV
authors.lastname: Postma
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Ivo A C
authors.initials: IA
authors.lastname: van der Bilt
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Baars
authors.affiliation: Department of Cardiology, Antonius Hospital, Sneek, the Netherlands.
authors.forename: Paul L
authors.initials: PL
authors.lastname: van Haelst
authors.affiliation: Department of Cardiology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Kadir
authors.initials: K
authors.lastname: Caliskan
authors.affiliation: Department of Genetics, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Hoedemaekers
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France; Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France; Université de Nantes, Nantes, France.
authors.forename: Solena
authors.initials: S
authors.lastname: Le Scouarnec
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France; Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France; Université de Nantes, Nantes, France; Centre Hospitalier Universitaire (CHU) Nantes, L'Institut du Thorax, Service de Cardiologie, Nantes, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Imke
authors.initials: I
authors.lastname: Christiaans
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Wilde
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: c.r.bezzina@amc.uva.nl.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D012804:Sick Sinus Syndrome / Q000151:congenital* / Q000000981:diagnostic imaging / Q000235:genetics; D013577:Syndrome; D014463:Ultrasonography; D055815:Young Adult
chemical_list: C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels
keywords: HCN4; exome sequencing; genetics; ion channel; left ventricular noncompaction cardiomyopathy; sinus bradycardia