Abstract
Hypertrophic cardiomyopathy (HCM) is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere proteins1–3. Other inheritable causes of the disease include mutations in genes coding for proteins important in calcium handling or that form part of the cytoskeleton4–6. At present, the primary clinical role of genetic testing in HCM is to facilitate familial screening to allow the identification of individuals at risk of developing the disease7,8. It is also used to diagnose genocopies, such as lysosomal9–11 and glycogen storage disease which have different treatment strategies, rates of disease progression and prognosis12–14. The role of genetic testing in predicting prognosis is limited at present, but emerging data suggest that knowledge of the genetic basis of disease will assume an important role in disease stratification15–17 and offer potential targets for disease-modifying therapy in the near future18.
Highlights
GENETIC ARCHITECTURE OF Hypertrophic cardiomyopathy (HCM) Familial HCM is characterized by locus and allelic heterogeneity, with a high frequency of novel individual mutations[7,19]
In 5–10% of cases, HCM is caused by mutations in genes that cause metabolic disorders[21,22,23], neuromuscular disease[24,25,26] or inherited genetic syndromes including Noonan syndrome[27,28,29] (Figure 1)
The myosin heavy chain head, with ADP and inorganic phosphate bound to its nucleotide-binding pocket, interacts with the exposed actin-binding sites followed by the release of ADP and inorganic phosphate, which occurs simultaneously with the power stroke
Summary
Mutations in ßMYH7 and MYBPC3 account for 60–70% of HCM patients with pathogenic variants[1,19,32,35]. The majority of disease-causing ß-myosin heavy chain mutations are found in one of four locations: the actin binding site, the nucleotide binding pocket, the hinge region adjacent to the binding site for two reactive thiols and in the α-helix close to the essential light chain interaction site[44]. It has been speculated that the HCM disease phenotype results from reduced contractile function caused by altered actin-myosin interactions, and consequent inappropriate compensatory hypertrophic remodelling[45,46]. Some MYH7 mutations are associated with increased cardiomyocyte mechanical contractile forces in vitro and show an increase in calcium sensitivity, leading to increases in tension generation and ATPase activity. Troponin-mutated mice exhibit severely impaired myocardial relaxation, independent of the degree of fibrosis, and consistent with the finding of increased calcium sensitivity[51,52,53].
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