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Published on: August 8, 2022
Genotype-phenotype correlations in hypertrophic cardiomyopathy: Insights from an HCM Center of Excellence
Muddasir Ashraf1, M Fuad Jan2, Arshad Jahangir2
1Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Aurora Health Care, 2801 W. Kinnickinnic River Parkway, Ste. 130, Milwaukee, WI 53215 USA.
Insights
Genetic testing in hypertrophic cardiomyopathy (HCM) reveals that genotype-positive patients have worse outcomes. Centers of Excellence are crucial for managing HCM patients effectively.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Gene distribution in hypertrophic cardiomyopathy (HCM) is dynamic due to new variant discoveries and reclassifications.
- The role of genotype in stratifying HCM patient risk remains unclear due to conflicting data.
Purpose of the Study:
- To analyze genotype distribution and genotype-phenotype correlations in adult HCM patients.
- To evaluate a composite outcome based on genotype status in HCM patients.
Main Methods:
- Genotyping was performed on 754 adult HCM patients over a 13-year period.
- A composite outcome including mortality, stroke, and heart failure events was assessed.
- All-cause mortality was analyzed separately based on genotype status.
Main Results:
- 27% of patients were genotype-positive (Gen-P), 22% had variants of unknown significance (VUS), and 51% were genotype-negative (Gen-N).
- MYBPC3 was the most frequently implicated gene (63%).
- Gen-P patients exhibited worse composite outcomes compared to Gen-N patients (HR 1.84, p<0.001).
Conclusions:
- MYBPC3 is the most common gene associated with HCM.
- Genotype-positive HCM patients experience poorer outcomes.
- Centers of Excellence are vital for optimizing medical management in HCM.
Background:
Owing to the recognition of previously unknown pathogenic gene variants and reclassification of longer-known variants, gene distribution in patients with hypertrophic cardiomyopathy (HCM) is ever-changing. Conflicting data make the role of genotype in risk stratification unclear.
Methods:
We evaluated genotype distribution and genotype-phenotype correlations in all adult patients with HCM seen at our HCM Center of Excellence from March 31, 2010, to April 30, 2023. We also evaluated a composite outcome, including all-cause mortality, stroke, implantable cardioverter-defibrillator placement, heart failure hospitalization, left ventricular assist device implantation, heart transplantation, septal myectomy, and alcohol septal ablation, based on genotype status. All-cause mortality was separately analyzed.
Results:
Of 827 patients with HCM, genotyping was completed in 754 (91.2 %). We identified 202 (27 %) genotype-positive (Gen-P), 163 (22 %) variant of unknown significance (VUS), and 389 (51 %) genotype-negative (Gen-N) patients. Mean ages were 47, 57, and 58 years, respectively. The most common gene implicated was MYBPC3 (63 %). More patients were on optimal medical treatment after following up with our HCM center. Electrocardiographic, Holter, echocardiographic, and cardiac magnetic resonance imaging characteristics differed based on genotype status. The composite outcome was worse in Gen-P than Gen-N (HR 1.84, p<0.001). Although analysis of all-cause mortality showed survival was different for Gen-P and VUS patients than for Gen-N patients, this difference was not statistically significant.
Conclusion:
MYBPC3 was the most common gene implicated. Outcomes were worse in Gen-P patients. Centers of Excellence play an important role in the optimal medical management of patients with HCM.
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