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HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy
Annalisa Milano1, Alexa M C Vermeer2, Elisabeth M Lodder1
1Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
Insights
Genetic mutations in HCN4 are linked to both bradycardia and left ventricular noncompaction cardiomyopathy (LVNC). This study identified HCN4 mutations as a shared cause for these combined cardiac conditions, revealing a new association for this ion channel gene.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Cardiac Diseases
Background:
- Familial sinus bradycardia is occasionally linked to mutations in HCN4, SCN5A, and ANK2, typically without structural heart defects.
- A subset of patients with sinus bradycardia also exhibit left ventricular noncompaction cardiomyopathy (LVNC), suggesting a potential shared genetic etiology.
- Previous research has not definitively established a common genetic cause for the co-occurrence of bradycardia and LVNC.
Purpose of the Study:
- To identify the specific genetic defect responsible for the combined presentation of bradycardia and LVNC.
- To investigate the hypothesis that a single genetic cause underlies both bradycardia and LVNC.
- To explore the role of HCN4 mutations in the pathogenesis of combined bradycardia and LVNC.
Main Methods:
- Exome sequencing was performed on two affected cousins from an index family presenting with bradycardia and LVNC.
- Single nucleotide polymorphism (SNP) array analysis identified shared chromosomal regions among five affected family members.
- Combined linkage analysis and exome sequencing pinpointed candidate variants, followed by segregation analysis and HCN4 gene screening in additional families.
Main Results:
- Exome sequencing and linkage analysis identified 11 novel shared variants in the index family, including a specific p.Gly482Arg mutation in the HCN4 gene.
- The identified HCN4 mutation segregated with the bradycardia-LVNC phenotype across the family.
- Screening of three additional families with similar clinical presentations revealed mutations in the HCN4 gene in all cases; electrophysiological studies confirmed impaired channel function.
Conclusions:
- Mutations in the HCN4 gene are implicated as a cause of familial sinus bradycardia.
- This study provides the first evidence linking HCN4 gene mutations to structural myocardial abnormalities, specifically left ventricular noncompaction cardiomyopathy.
- HCN4 mutations represent a shared genetic cause for the combined clinical features of bradycardia and LVNC.
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.
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