Objective: The aim of this study was to identify the genetic defect underlying the combined clinical presentation of bradycardia and left ventricular noncompaction cardiomyopathy (LVNC), hypothesizing that these two clinical abnormalities have a common genetic cause.
Background: Familial forms of primary sinus bradycardia have in some cases 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 LVNC pointing to a shared genetic cause.
Methods: Exome sequencing was carried out in two 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 five affected family members that were identified using SNP-array analysis.
Results: The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the two affected cousins. One of these, p.G482R in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in three additional families, with the same clinical combination of bradycardia and LVNC, identified HCN4 mutations in all three. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage-dependency of activation, consistent with the observed bradycardia.
Conclusions: While mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence that mutations in this ion channel gene may also associate with structural abnormalities of the myocardium.