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Phenotype and Outcomes in Rare Genetic Variants of HCM
Quick Takes
- In a large prospectively enrolled registry of middle-aged adults, prevalence of a pathogenic or likely pathogenic sarcomeric gene mutation was 0.25%. Disease penetrance was 18%.
- The risk for all-cause mortality and MACE was higher in genotype-positive compared to genotype-negative individuals, irrespective of presence of cardiomyopathy.
- The genotypic risk with pathogenic/likely pathogenic sarcomeric mutations was higher in women compared to men.
Study Questions:
What are cardiovascular phenotypes and outcomes associated with rare variants in sarcomere-encoding genes in middle-aged adults?
Methods:
Participants prospectively enrolled in the UK BioBank who underwent whole exome sequencing (WES) were studied. The cohort was divided into three groups: 1) genotype negative if there was no rare protein-altering genetic variation in any of the 25 genes that may cause or mimic hypertrophic cardiomyopathy (HCM); 2) genotype positive if pathogenic/likely pathogenic rare variant is noted in the eight genes associated with HCM; 3) genotype indeterminate if other rare genetic variants were present without adequate data to classify them as pathogenic/likely pathogenic. Endpoints of interest included all-cause mortality or composite of heart failure, stroke, arrhythmia, or cardiac arrest (major adverse cardiovascular events [MACE]).
Results:
A total of 200,584 participants underwent WES and 39,551 had cardiac magnetic resonance imaging (MRIs). Overall, 157,922 were genotype negative, 493 (0.25%) were genotype positive, and 5,219 (2.6%) were genotype indeterminate. Among participants who had a cardiac MRI, phenotypic HCM was noted in 76 (0.19%). When analysis was restricted to all participants with both WES and MRI, compared to genotype negative, wall thickness in genotype positive and genotype indeterminate was greater. Penetrance in genotype positive was 18.4% for HCM and 2.9% in genotype indeterminate. Prevalence of left ventricular systolic dysfunction was no different between the three groups.
Clinical outcomes were assessed in 163,634 participants with a median follow-up of 10.8 years. Genotype-positive participants had an increased risk of death or MACE (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.38-2.07), heart failure (HR, 4.23; 95% CI, 3.07-5.83), and arrhythmia (HR, 1.59; 95% CI, 1.22-2.09) compared to genotype-negative participants. These associations persisted despite exclusion of individuals with known cardiomyopathy. Outcomes were not different between genotype-indeterminate and genotype-negative participants. Incremental genotypic risk from pathogenic mutation was higher in females than in males. The risk for heart failure was higher in genotype-positive compared to genotype-negative participants despite adjustment for wall thickness (HR, 8.05; 95% CI, 2.46-26.3).
Conclusions:
In a large, prospective registry of middle-aged adults, prevalence of pathogenic/likely pathogenic sarcomeric mutations was noted in 0.25% of participants. The penetrance for HCM phenotype in genotype-positive participants was 18%. The risk for death and MACE was elevated in genotype-positive compared to genotype-negative participants. This risk was higher for women compared to men. Genotype-indeterminate individuals in comparison had a clinically benign course.
Perspective:
Most individuals with pathogenic or likely pathogenic mutations in sarcomeric genes do not have overt HCM. In this study, the prevalence of a pathogenic/likely pathogenic variant in sarcomeric genes was noted in 1 in 407 adults. This translates to over 18 million people worldwide. Penetration of HCM was modest at 18% in these individuals. However, most importantly, presence of such a mutation correlated with a substantially higher risk for all-cause mortality and MACE compared to genotype-negative individuals even in the absence of a cardiomyopathy. In addition, this genotypic risk was higher in women compared to men, suggesting that women fare worse than men. These findings suggest that although phenotypic manifestation is rare with these variants, they may enhance risk stratification even in the absence of a cardiomyopathy.
Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Magnetic Resonance Imaging
Keywords: Arrhythmias, Cardiac, Cardiomyopathies, Cardiomyopathy, Hypertrophic, Genetic Variation, Genotype, Heart Arrest, Heart Failure, Magnetic Resonance Imaging, Middle Aged, Mutation, Phenotype, Risk Assessment, Sarcomeres, Stroke, Whole Exome Sequencing
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