HCN4 Mutations in Multiple Families With Bradycardia and Left Ventricular Noncompaction Cardiomyopathy

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:64

Article

Milano, Annalisa¹  Vermeer, Alexa M. C.²  Lodder, Elisabeth M.¹  Barc, Julien^1,3  Verkerk, Arie O.⁴  Postma, Alex V.⁴  van der Bilt, Ivo A. C.¹  Baars, Marieke J. H.²  van Haelst, Paul L.⁵  Caliskan, Kadir⁶  Hoedemaekers, Yvonne M.⁷  Le Scouarnec, Solena^8,9,10  Redon, Richard^8,9,10,11  Pinto, Yigal M.¹  Christiaans, Imke²  Wilde, Arthur A.¹  Bezzina, Connie R.¹ 

[1] Univ Amsterdam, Acad Med Ctr, Dept Clin & Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands

[2] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands

[3] ICIN Netherlands Heart Inst, Utrecht, Netherlands

[4] Univ Amsterdam, Acad Med Ctr, Dept Anat Embryol & Physiol, NL-1105 AZ Amsterdam, Netherlands

[5] Antonius Hosp, Dept Cardiol, Sneek, Netherlands

[6] Erasmus MC, Dept Cardiol, Rotterdam, Netherlands

[7] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands

[8] Inst Thorax, INSERM, UMR 1087, Nantes, France

[9] CNRS, UMR 6291, Nantes, France

[10] Univ Nantes, Nantes, France

[11] CHU Nantes, Inst Thorax, Serv Cardiol, F-44035 Nantes 01, France

关键词: exome sequencing;    genetics;    HCN4;    ion channel;    left ventricular noncompaction cardiomyopathy;    sinus bradycardia;   

DOI  :  10.1016/j.jacc.2014.05.045

来源: Elsevier

【 摘 要 】

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. (C) 2014 by the American College of Cardiology Foundation.

【 授权许可】

Free