Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy

Abstract

Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle that occurs mainly due to mutations (>1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people in the general population, is typically inherited in an autosomal dominant pattern, and presents variable expressivity and age-related penetrance. Due to the morphological and pathological heterogeneity of the disease, the appearance and progression of symptoms is not straightforward. Most HCM patients are asymptomatic, but up to 25% develop significant symptoms, including chest pain and sudden cardiac death. Sudden cardiac death is a dramatic event, since it occurs without warning and mainly in younger people, including trained athletes. Molecular diagnosis of HCM is of the outmost importance, since it may allow detection of subjects carrying mutations on HCM-associated genes before development of clinical symptoms of HCM. However, due to the genetic heterogeneity of HCM, molecular diagnosis is difficult. Currently, there are mainly four techniques used for molecular diagnosis of HCM, including Sanger sequencing, high resolution melting, mutation detection using DNA arrays, and next-generation sequencing techniques. Application of these methods has proven successful for identification of mutations on HCM-related genes. This review summarizes the features of these technologies, highlighting their strengths and weaknesses. Furthermore, current therapeutics for HCM patients are correlated with clinically observed phenotypes and are based on the alleviation of symptoms. This is mainly due to insufficient knowledge on the mechanisms involved in the onset of HCM. Tissue engineering alongside regenerative medicine coupled with nanotherapeutics may allow fulfillment of those gaps, together with screening of novel therapeutic drugs and target delivery systems.

Keywords: hypertrophic cardiomyopathy; molecular diagnosis; next-generation sequencing; sarcomere; sudden cardiac death.

Figure 1

Schematic representation of heart failure due to sarcomeric/intrasarcomeric mutations. Mutations in the proteins responsible for the maintenance of sarcomere structure and function result in inefficient or excessive use of ATP and a consequent energy deficiency. The energy requirements then compromise calcium homeostasis in the cell, resulting in, among other events, an increase in calcium sensitivity of the ATPase SERCA and increased cytosolic free calcium. The contractibility of the myocyte is then compromised, ultimately resulting in cell death and consequent myocardial fibrosis. This myocardial fibrosis and further ischemia may result in left ventricular hypertrophy, increasing the risk of heart failure. Abbreviations: NCX, sodium–calcium exchanger; DHPR, dihydropyridine receptor; Ryr, ryanodide receptor; SERCA, sarco/endoplasmic reticulum Ca2⁺-ATPase; AMP, adenosine monophosphate; ATP, adenosine triphosphate.

Figure 2

Morphological features of a normal heart and a heart with left ventricular hypertrophy.