Annalisa Milano1, Alexa M C Vermeer2, Elisabeth M Lodder1, Julien Barc3, Arie O Verkerk4, Alex V Postma4, Ivo A C van der Bilt1, Marieke J H Baars2, Paul L van Haelst5, Kadir Caliskan6, Yvonne M Hoedemaekers7, Solena Le Scouarnec8, Richard Redon9, Yigal M Pinto1, Imke Christiaans2, Arthur A Wilde1, Connie R Bezzina10. 1. Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. 2. Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands. 3. Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands; ICIN-Netherlands Heart Institute, Utrecht, the Netherlands. 4. Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, the Netherlands. 5. Department of Cardiology, Antonius Hospital, Sneek, the Netherlands. 6. Department of Cardiology, Erasmus MC, Rotterdam, the Netherlands. 7. Department of Genetics, University Medical Centre Groningen, Groningen, the Netherlands. 8. 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. 9. 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. 10. Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: c.r.bezzina@amc.uva.nl.
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. OBJECTIVES: 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.
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. OBJECTIVES: 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: Preeti Ramachandran; Jessica G Woo; Thomas D Ryan; Roosevelt Bryant; Haleh C Heydarian; John L Jefferies; Jeffrey A Towbin; Angela Lorts Journal: Pediatr Cardiol Date: 2016-06-29 Impact factor: 1.655