What Causes Hypertrophic Cardiomyopathy?

Abstract

Hypertrophic cardiomyopathy (HCM) is a global and relatively common cause of patient morbidity and mortality and is among the first reported monogenic cardiac diseases. For 30 years, the basic etiology of HCM has been attributed largely to variants in individual genes encoding cardiac sarcomere proteins, with the implication that HCM is fundamentally a genetic disease. However, data from clinical and network medicine analyses, as well as contemporary genetic studies show that single gene variants do not fully explain the broad and diverse HCM clinical spectrum. These transformative advances place a new focus on possible novel interactions between acquired disease determinants and genetic context to produce complex HCM phenotypes, also offering a measure of caution against overemphasizing monogenics as the principal cause of this disease. These new perspectives in which HCM is not a uniformly genetic disease but likely explained by multifactorial etiology will also unavoidably impact how HCM is viewed by patients and families in the clinical practicing community going forward, including relevance to genetic counseling and access to healthcare insurance and psychosocial wellness.

Figure 1.

Determinants of HCM. (A) Distribution of variants in genes coding for sarcomere proteins in patients with HCM assessed in clinical practice. It is notable that 50% of HCM patients have no sarcomere gene mutation. However, only 30% of consecutive HCM patients have mutations that can be considered pathogenic (disease-causing). (B) Prevalence of putative HCM-causing gene variants is greater than expected in large genetic databases comprising non-affected populations: TNNT2 (K247R), OBSCN (R4344Q), TNNI3 (P82S), MYBPC3 (G278E), and JPH2 (G505S) are top 5 most common gene variants inappropriately defined as pathogenic, and account for most (74%) of HCM diagnoses judged misclassified. Reproduced with permission from Manrai et al. (C) Recent data from the Seidman laboratory shows widely divergent HCM phenotypes in monozygotic twins, supporting the hypothesis that factors other than genotype are critical to understanding the totality of HCM. Ventricular septal thickness on echocardiographic imaging differs substantially in the twins. Reproduced from Repetli GG, et al with permission. (D) Network features, emphasizing that network connections represent functionally important protein-protein interactions (PPIs). (E, F) Using myectomy specimens from patients with obstructive HCM, PPI networks are dense, complex, and vary widely between patients, suggesting that sarcomere genes alone are unlikely to explain the pathogenesis of this disease. Network topology was not informed by putative HCM-causing sarcomere genes, which in fact represented only <0.1% of all network features. Two representative patient networks are shown, which underscore: (i) HCM pathobiology is complex and (ii) a vast majority of functionally important molecular signaling pathways do not involve any of 17 genes commonly designated as HCM disease-causing (red arrows). Images derived from methods and results reported originally in Maron et al.Heterogeneity in PPI networks is akin to differences observed in wiring maps of other complex systems.

Figure 2.

HCM is a disease of converging endophenotypes, regulated by complex interaction between genetic, post-transcriptional, and environmental determinants. (A) Genetic, biological, acquired, and social profiles likely influence individual functional protein-protein interaction patterns in individual patients with HCM. (B) This paradigm sets the framework for a model that integrates genetic context with environmental determinants of disease to explain HCM. Cross-talk among PPIs between endophenotypes, which may vary between patients, explains heterogeneity in clinical phenotypes evident in HCM populations. EPA = epidemiologic-pathological axis.