Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).

Background: A better understanding of the factors that contribute to heterogeneous outcomes and lifetime disease burden in hypertrophic cardiomyopathy (HCM) is critically needed to improve patient management and outcomes. The Sarcomeric Human Cardiomyopathy Registry (SHaRe) was established to provide the scale of data required to address these issues, aggregating longitudinal datasets curated by eight international HCM specialty centers. Methods: Data on 4591 HCM patients (2763 genotyped), followed for a mean of 5.4±6.9 years (24,791 patient-years; median [interquartile range] 2.9 [0.3-7.9] years) were analyzed regarding cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator (ICD) therapy, all-cause death, atrial fibrillation, stroke, New York Heart Association Functional Class III/IV symptoms (all comprising the overall composite endpoint), and left ventricular ejection fraction (LVEF)<35%. Outcomes were analyzed individually and as composite endpoints. Results: Median age of diagnosis was 45.8 [30.9-58.1] years and 37% of patients were female. Age of diagnosis and sarcomere mutation status were predictive of outcomes. Patients <40 years old at diagnosis had a 77% [95% confidence interval: 72%, 80%] cumulative incidence of the overall composite outcome by age 60, compared to 32% [29%, 36%] by age 70 for patients diagnosed >60 years. Young HCM patients (20-29 years) had 4-fold higher mortality than the general United States population at a similar age. Patients with pathogenic/likely pathogenic sarcomere mutations had two-fold greater risk for adverse outcomes compared to patients without mutations; sarcomere variants of uncertain significance were associated with intermediate risk. Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis. Ventricular arrhythmias occurred in 32% [23%, 40%] of patients <40 years at diagnosis, but in 1% [1%, 2%] >60 years. Conclusions: The cumulative burden of HCM is substantial and dominated by heart failure and atrial fibrillation occurring many years following diagnosis. Young age of diagnosis and the presence of a sarcomere mutation are powerful predictors of adverse outcomes. These findings highlight the need for close surveillance throughout life, and the need to develop disease-modifying therapies.

Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.

BACKGROUND: The clinical significance of variants in genes associated with inherited cardiomyopathies can be difficult to determine because of uncertainty regarding population genetic variation and a surprising amount of tolerance of the genome even to loss-of-function variants. We hypothesized that genes associated with cardiomyopathy might be particularly resistant to the accumulation of genetic variation. METHODS AND RESULTS: We analyzed the rates of single nucleotide genetic variation in all known genes from the exomes of >5000 individuals from the National Heart, Lung, and Blood Institute's Exome Sequencing Project, as well as the rates of structural variation from the Database of Genomic Variants. Most variants were rare, with over half unique to 1 individual. Cardiomyopathy-associated genes exhibited a rate of nonsense variants, about 96.1% lower than other Mendelian disease genes. We tested the ability of in silico algorithms to distinguish between a set of variants in MYBPC3, MYH7, and TNNT2 with strong evidence for pathogenicity and variants from the Exome Sequencing Project data. Algorithms based on conservation at the nucleotide level (genomic evolutionary rate profiling, PhastCons) did not perform as well as amino acid-level prediction algorithms (Polyphen-2, SIFT). Variants with strong evidence for disease causality were found in the Exome Sequencing Project data at prevalence higher than expected. CONCLUSIONS: Genes associated with cardiomyopathy carry very low rates of population variation. The existence in population data of variants with strong evidence for pathogenicity suggests that even for Mendelian disease genetics, a probabilistic weighting of multiple variants may be preferred over the single gene causality model.