Genetic advances in sarcomeric cardiomyopathies: state of the art

Abstract

Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine.

Differentiating physiology from pathology in elite athletes. Left ventricular hypertrophy versus hypertrophic cardiomyopathy

“…These genes are also considered to be determinants of HCM; so-called distant-acting modifiers. This phenomenon, independently of a direct genetic mutation, is in part responsible for the great phenotypic diversity observed in HCM, besides locally acting modifiers, epigenetic mechanisms, and environmental factors [22].…”

“…Among these, most common are mutations that affect sarcomere proteins [22]. In 1990, a mutation responsible for HCM was identified in the beta-myosin heavy chain (MYH7) gene.…”

“…Most of these genes encode proteins of myofilaments or the Z-disc of the sarcomeres. As such, HCM has been described as 'a disease of the sarcomere', and this aetiology is most often considered in a case of LVH that is not explained by increased loading conditions [22].…”

Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

“…This phenotypic overlap demonstrates the clinical complexity of cardiomyopathy, and the variable expressivity from well over 1000 mutations in over 100 known cardiomyopathy genes [6] . Typically, these genes encode proteins of the sarcomere, z-disk domain, intermediate filaments, ion channel, intercalated disk, and cytoskeletal proteins [3,[7][8][9][10] . This variable expressivity in cardiomyopathy is seen even within the same family, with multiple diagnoses (including this family and other examples) [7,9,11,12] .…”

Fabry Disease and/or Hypertrophic Cardiomyopathy

“…More than 1400 mutations have been described in association with HCM. [1][2][3][8][9][10][11] Article p.454…”