Studies over the last 30 years have identified hypertrophic cardiomyopathy (HCM) as predominantly an autosomal dominant disorder caused by disease-causing variants in genes encoding the sarcomere proteins critical for contractile function. The two most common disease genes implicated are the MYBPC3 and MYH7 genes, with disease-causing variants in these two genes accounting for 70-80% of all genotype-positive HCM patients. This increased knowledge of the genetic basis of HCM has heralded the era of precision medicine, with genetic testing leading to more improved and precise diagnosis, effective cascade genetic testing in at-risk family members, assistance with reproductive decisions, targeted therapeutics guided by both phenotype and genotype, and providing important insights into risk stratification and prognosis. Most recently, novel insights into genetic mechanisms have been elucidated, spanning non-Mendelian aetiologies, non-familial forms of HCM, and development of polygenic risk scores. These advances have laid the platform for exciting future endeavours such as newer gene therapy approaches in HCM, including gene replacement studies and genome editing approaches to ultimately cure disease. This brief review summarises the current role of genetic testing in HCM patients and families, and introduces some new mechanistic insights leading to the consideration of gene therapy approaches for HCM.

Cardiomyopathies are a heterogeneous heart diseases group in terms of morphology and aetiology. Hypothesising a tropical specificity and given an absence of data in French Guiana, the primary objective of our study was to describe morphologies and aetiologies of cardiomyopathies observed at Cayenne General Hospital. A cross-sectional study was conducted in Cayenne Hospital from 1 January 2009 to 1 June 2014 in the hospital database. Only patients with the definition of the European Society of Cardiology (ESC) were included, based on the first transthoracic ultrasonography found during the study period. Medical files were consulted. With 182 patients included, the prevalence of cardiomyopathies among heart diseases was estimated at 4.3% (95% CI 3.7% to 4.9%). Twelve patients had a familial or genetic aetiology (6.6%) and 170 a non-familial or non-genetic aetiology (93.4%). The morphological spectrum was: dilated for 114 patients (62.6%), hypertrophic for 27 (14.8%), unclassified for 1 (0.5%) and non-classifiable for 13 (7.1%). This group was constituted of patients with a systolic and/or diastolic functional impairment without morphological abnormality. The aetiological spectrum found 184 aetiologies including: 70.9% undetermined, 8.7% infectious (with 6.5% chagasic and 0.5% related with human immunodeficiency virus) and 6.0% with toxins. Cardiomyopthies are a common and severe clinical problem. The frequency of infectious aetiologies and dilated impairment are arguments for cardiomyopathies with tropical particularities. However, the preponderance of undetermined aetiologies justifies the development of further research programmes.

Cardiomyopathies affect more than 0.5% of the general population. They are associated with high risk of sudden cardiac death, which can result from either heart failure or electrical abnormalities. Although different mechanisms underlie the various types of cardiomyopathies, a principal pathology is common to all and is usually at the level of the cardiac muscle. With a relatively high incidence rate in most countries, and a subsequent major health burden on both the families and governments, cardiomyopathies are gaining more attention by researchers and pharmaceutical companies as well as health government bodies. In Lebanon, there is no official data about the spectrum of the diseases in terms of their respective prevalence, clinical, or genetic profiles. We used exome sequencing to unravel the genetic basis of idiopathic cases of cardiomyopathies in Lebanon, a relatively small country with high rates of consanguineous marriages. Five cases were diagnosed with different forms of cardiomyopathies, and exome sequencing revealed the presence of already documented or novel mutations in known genes in three cases: LMNA for an Emery Dreifuss Muscular Dystrophy case, PKP2 for an arrhythmogenic right ventricle dysplasia case, and MYPN for a dilated cardiomyopathy case. Interestingly two brothers with hypertrophic cardiomyopathy have a novel missense variation in NPR1, the gene encoding the natriuretic peptides receptor type I, not reported previously to be causing cardiomyopathies. Our results unravel novel mutations in known genes implicated in cardiomyopathies in Lebanon. Changes in clinical management however, require genetic profiling of a larger cohort of patients.

There has been a progressive evolution in systems of classification for cardiomyopathy, driven by advances in imaging modalities, disease recognition, and genetics, following initial clinical descriptions in the 1960s. A pathophysiological classification emerged and was endorsed by World Health Organisation Task Forces in 1980 and 1995: dilated, hypertrophic, restrictive, and arrhythmogenic right ventricular cardiomyopathies; subdivided into idiopathic and disease-specific cardiomyopathies. Genetic advances have increasingly linked "idiopathic" phenotypes to specific mutations, although most linkages exhibit highly variable or little genotype-phenotype correlation, confounded by age-dependent changes and varying penetrance. The following two dominant classification systems are currently in use, with advocates in both continents. First, American Heart Association (2006): "A heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually exhibit inappropriate ventricular hypertrophy or dilatation due to a variety of causes that frequently are genetic". These are subdivided to those predominantly involving the heart - primary - due to genetic mutation, including ion channelopathies, acquired disease, or mixed; and those with systemic involvement in other organ systems - secondary. Second, European Society of Cardiology (2008): "A myocardial disorder in which heart muscle is structurally and functionally abnormal… sufficient to cause the observed myocardial abnormality", with subdivision to familial and non-familial, excluding ion channelopathies, and split to specific disease subtypes and idiopathic. Further differences exist in the definitions for hypertrophic cardiomyopathy; however, whichever high-level classification is used, the clinical reality remains phenotype driven. Clinical evaluation and diagnostic imaging dominate initial patient contact, revealing diagnostic red flags that determine further specific tests. Genetic testing is undertaken early. A recent attempt to harmonise these competing systems named the MOGE(S) system, based on descriptive logical nosology, currently remains unproven as a fully practical solution.