New Gene Identified as a Driver in Hypertrophic Cardiomyopathy

A recently discovered gene has been found to have an impact on the severity of hypertrophic cardiomyopathy (HCM), a chronic, progressive disease in which excessive contraction of the heart muscle can lead to the development of debilitating symptoms and cardiac dysfunction.

Investigators have found that a rare variant of the Alpha-protein kinase 3 (ALPK3) can cause a severe type of HCM. In a study published recently in European Heart Journal, Luis R. Lopes of the University College London and St. Bartholomew’s Hospital and his colleagues found that truncating variants in ALPK3 (ALPK3tv) occurred in just 1.56% of the 770 patients in a discovery cohort and 1.56% of a larger validation cohort of 2,047 patients. But these were the patients who were more likely to have apical HCM, a rare form of the disease, have more extensive fibrosis, and are more likely to progress to heart failure.

In patients with HCM, the heart muscle becomes abnormally thick, making it harder for the heart to pump blood. The thickened heart muscle can cause shortness of breath, chest pain, or problems in the heart’s electrical system, resulting in life-threatening arrhythmias or sudden death.

In the obstructive disease form of the disease, the thickened heart wall can block or reduce the flow of blood from the left ventricle to the aorta. Of those diagnosed, two-thirds have the obstructive form of the disease.

It’s estimated that 1 in every 500 people have HCM, but a large percentage of patients are undiagnosed, according to the American Heart Association.

Lopes and his colleagues confirmed that ALPK3tv is a variant of interest in HCM. ALPK3tv carriers had distinctive patterns of left ventricular hypertrophy, with apical or concentric patterns more prevalent; 60% of ALPK3tv carriers had apical/concentric hypertrophy compared with 13% of sarcomere-positive and 35% of sarcomere-negative cases.

Almost half of the patients with ALPK3tv had extensive fibrosis on cardiac magnetic resonance. About one-fourth of were at high risk for sudden cardiac death and were referred for an implantable cardioverter-defibrillator and one-eighth had left ventricular systolic dysfunction at baseline or during follow-up, and almost 10% were referred for cardiac transplantation.

Investigators also found the odds ratio for patients with South Asian ancestry was 44.75 compared with 10.92 for white patients, but they said this will need to be confirmed in further studies.

“The penetrance of such variants in the general population is likely to be substantially lower. Based on a case prevalence of 1.6%, we can estimate the population-level penetrance for ALPK3tv to be just 3.3%,” the editors of European Heart Journal wrote in an accompanying editorial. “This is in contrast to the predominant HCM loss-of-function gene MYBPC3, which has an estimated population-level penetrance of about 20%.”

The editors suggest its critical to assess a range of genetic factors when evaluating disease risk in patients and families.