Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy

Background Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population. Objectives The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults. Methods This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status. Results The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001). Conclusions In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.

H ypertrophic cardiomyopathy (HCM) is characterized by clinical and genetic heterogeneity, incomplete and age-dependent penetrance, and variable expressivity (1). Most individuals with HCM have a normal life expectancy but are at increased risk of adverse outcomes such as heart failure, atrial fibrillation, stroke, or sudden cardiac death (2). Here, we sought to determine the population prevalence of rare sarcomeric variants in a prospectively recruited cohort of >200,000 middle-age participants drawn from the UK Biobank (UKBB) and to assess lifetime risk of adverse events. We analyzed  Table 1.

CARDIAC PHENOTYPING USING MACHINE LEARNING.
Participants in the imaging substudy were randomly invited, and the response rates with exclusion criteria have been previously reported (11). Each underwent CMR at 1.5-T (12). Segmentation of the cine images was performed by using a deep learning neural network algorithm developed in-house and optimized on the UKBB cohort. The performance of image annotation using this algorithm is equivalent to a consensus of expert human readers and achieves subpixel accuracy for cardiac segmentation (13).
Myocardial wall thickness (WT) was measured along radial line segments connecting the endocardial and epicardial surfaces perpendicular to the myocardial center-line and excluding trabeculae (Figure 1), an approach that also exceeds the reliability of human experts (14). Chamber volumes and mass were calculated from the segmentations according to standard post-processing guidelines (15). Myocardial strain analysis was performed by using nonrigid free-form deformation image registration (16,17).   Trabecular traits were quantified by using fractal dimension analysis in which a higher value indicates more complex trabeculation (18). Parametric 3-dimensional analysis of the geometry of the left ventricle was performed to map regional patterns of remodeling and quantify the association with genetic and environmental predictors (16,(19)(20)(21).
Further details on phenotyping are given in the Supplemental Appendix.

DISCUSSION
In this study of >200,000 adults, we found the preva-       In 200,000 adults, the prevalence of variants pathogenic or likely pathogenic for hypertrophic cardiomyopathy (SARC-HCM-P/LP) was 1 in 407, whereas the aggregate prevalence of indeterminate sarcomeric variants was 1 in 38. The SARC-HCM-P/LP variants were associated with increased risk of death and major adverse cardiovascular events. We found associations with hypertrophic cardiomyopathy-like imaging phenotypes although the prevalence of overt cardiomyopathy was low.
SARC-IND ¼ indeterminate variants in hypertrophic cardiomyopathy-associated sarcomere-encoding genes (rare variants that do not meet criteria for pathogenic/ likely pathogenic annotation); SARC-NEG ¼ genotype negative.
de Marvao et al.
unexplained LVH and managing the appropriate screening of relatives (2). STUDY LIMITATIONS. UKBB is a large-cross sectional study that is subject to selection bias, excluding younger and potentially more severe cases (44); however, risk factor associations seem to be broadly generalizable (45). The population is predominantly European, and further work is required to explore traits and outcomes in people of diverse ancestries.
Although we included outcome data before enroll-