Alexa M.C. Vermeer

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

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.

Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations

AIMS Disease mechanisms regarding hypertrophic cardiomyopathy (HCM) are largely unknown and disease onset varies. Sarcomere mutations might induce energy depletion for which until now there is no direct evidence at sarcomere level in human HCM. This study investigated if mutations in genes encoding myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7) underlie changes in the energetic cost of contraction in the development of human HCM disease. METHODS AND RESULTS Energetic cost of contraction was studied in vitro by measurements of force development and ATPase activity in cardiac muscle strips from 26 manifest HCM patients (11 MYBPC3mut, 9 MYH7mut, and 6 sarcomere mutation-negative, HCMsmn). In addition, in vivo, the ratio between external work (EW) and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined in 28 pre-hypertrophic mutation carriers (14 MYBPC3mut and 14 MYH7mut) and 14 healthy controls using [(11)C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Tension cost (TC), i.e. ATPase activity during force development, was higher in MYBPC3mut and MYH7mut compared with HCMsmn at saturating [Ca(2+)]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca(2+)]. EW was significantly lower in both mutation carrier groups, while MVO2 did not differ. MEE was significantly lower in both mutation carrier groups compared with controls, showing the lowest efficiency in MYH7 mutation carriers. CONCLUSION We provide direct evidence that sarcomere mutations perturb the energetic cost of cardiac contraction. Gene-specific severity of cardiac abnormalities may underlie differences in disease onset and suggests that early initiation of metabolic treatment may be beneficial, in particular, in MYH7 mutation carriers.

Ebstein anomaly associated with left ventricular noncompaction: An autosomal dominant condition that can be caused by mutations in MYH7

Left ventricular noncompaction (LVNC) is a relatively common genetic cardiomyopathy, characterized by prominent trabeculations with deep intertrabecular recesses in mainly the left ventricle. Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD). The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum. Several reports of sporadic as well as familial cases of Ebstein anomaly associated with LVNC have been reported. Recent studies identified mutations in the MYH7 gene, encoding the sarcomeric β‐myosin heavy chain protein, in patients harboring this specific phenotype. Here, we will review the association between Ebstein anomaly, LVNC and mutations in MYH7, which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance.

Dilation of the Aorta Ascendens Forms Part of the Clinical Spectrum of HCN4 Mutations

The HCN4-channel conducts the hyperpolarization-activated pacemaker current (“funny” current, If) in the sinoatrial node and mutations in the HCN4 gene are a long recognized genetic cause of sinus bradycardia [(1)][1]. Recently, the phenotypic spectrum of HCN4 mutations has been extended with

An International External Validation Study of the 2014 European Society of Cardiology Guideline on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy (Evidence from HCM)

Background: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. Methods: This was an observational, retrospective, longitudinal cohort study. Results: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9–3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93–1.12), C-index of 0.70 (95% CI, 0.68–0.72), and D-statistic of 1.17 (95% CI, 1.05–1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8–2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96–13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD. Conclusions: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.

Familial Disease Is Not Always Genetic: A Family With Atrioventricular Block and Mitral Regurgitation

We present a family from a founder population referred for cardiogenetic evaluation for atrioventricular block in 3 siblings. Genetic testing, including whole-exome sequencing, did not identify a disease-causing mutation. After reconsidering the differential diagnosis, a nongenetic cause was identified. This case highlights the importance of a thorough clinical evaluation even when a genetic cause is seemingly obvious.

Transthyretin amyloidosis: a phenocopy of hypertrophic cardiomyopathy.

Abstract Objectives: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder that affects over one in 500 persons worldwide. The autosomal dominant transmission of HCM implies that many relatives are at risk for HCM associated morbidity and mortality, therefore genetic testing and counselling is of great importance. However, in only 50–60% of the patients a mutation is found, which hampers predictive genetic testing in relatives. In HCM patients in whom the causal mutation has not been identified (yet), phenocopies of HCM – i.e. diseases that mimic HCM – could be responsible for the HCM phenotype. One of the HCM phenocopies is transthyretin amyloidosis (ATTR), caused by mutations in the transthyretin (TTR) gene. Methods: From 697 HCM index patients referred to our cardiogenetics outpatient clinic and tested for HCM associated genes between January 1997 and December 2012, we selected the ones without a detected causal mutation (n = 345). In these patients, additional DNA analysis of the TTR gene was performed. Results: In four patients (1.2%), a TTR mutation was detected (E7G, V30M, T119M, V122I). The E7G mutation is probably a non-pathogenic mutation. The T119M mutation is a known TTR mutation, but does not cause a cardiac phenotype. So in two (0.6%) patients, TTR analysis identified the cause of their HCM. Conclusions: ATTR should always be considered in patients with unexplained HCM, especially because of the great benefit of an early diagnosis regarding treatment and prognosis.

Letter by Vermeer et al Regarding Article, “Phenotypic Spectrum of HCN4 Mutations: A Clinical Case”

With interest, we read the article by Servatius et al1 presenting a 36-year-old man with sick sinus syndrome, left ventricular noncompaction, mood and anxiety disorders, and ventricular fibrillation because of …

Human Genetics of Cardiomyopathies

Over the past few decades, there has been notable progress in knowledge and implication of genetics in cardiomyopathies. Twenty-five years ago we started to recognize the genes; nowadays dozens ‑of genes associated with cardiomyopathies have been described. Genes and specific mutations can be unique for a certain cardiomyopathy or have specific phenotypic characteristics, but most genes, especially genes encoding for sarcomeric proteins, are associated with different cardiomyopathy subtypes. The large variability in disease penetrance, in disease symptoms and prognosis, and in some families even in cardiomyopathy subtype makes genetic counseling of great importance. Finding a causal mutation in a patient allows identification of relatives at risk of cardiomyopathy and enables presymptomatic assessment of the risk on sudden cardiac death (SCD). The advent of next-generation sequencing (NGS) techniques like cardiogenetic gene panels with sequencing of dozens of genes in one go does not only improve detection of causal mutations but also increases the chance of variants of unknown significance (VUS). These VUS make genetic counseling even more important and challenging. Reclassification of VUS into benign variants, disease modifiers, or causal mutations will be the main focus of research in coming years.