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Clinical outcomes of MYBPC3 variant carriers in a diverse cohort of patients with hypertrophic cardiomyopathy

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical-Adult
  • Secondary Categories:
    • Clinical-Adult & Pediatric
Introduction:
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, with MYBPC3 being the most frequently mutated gene. Despite its prevalence, there has been significant variability in the outcomes described in MYBPC3 genotype-positive patients with HCM. Furthermore, prior studies have been predominantly composed of patients of European ancestry. Therefore, we sought to examine variant types and location in MYBPC3 in our diverse cohort of patients with HCM and to evaluate outcomes of patients based on variant status.

Methods:
This prospective single-center cohort study was conducted under Institutional Board Review approval and compared the incidence of major adverse cardiovascular events (MACE) based on MYBPC3 variant status in patients with HCM. For the primary analysis, patients were divided into two groups: those with pathogenic/likely pathogenic variants in MYBPC3 (“genotype positive”) versus those with VUS, likely benign/benign, or negative genetic testing (“genotype negative”). The primary outcome of incident MACE was defined as a composite of new-onset arrhythmias, stroke, increase in New York Heart Association functional class by ≥1 class, heart transplant or left ventricular assist device implantation, hospitalization for HCM-related morbidities, and cardiovascular mortality. As a secondary analysis, genotype-positive patients with MYBPC3 were compared to genotype-positive patients with MYH7.

Results:
A total of 336 patients underwent clinical multigene panel testing between 2009-2023 in our cohort of 1,043 patients with HCM. 53 patients were found to have pathogenic/likely pathogenic variants in MYBPC3, 20 patients had VUS, 139 had a pathogenic/likely pathogenic/VUS in a separate cardiomyopathy gene, and 124 patients had benign variants/negative genetic testing in MYBPC3. Therefore, 197 patients were included in our primary analysis: 53 “genotype-positive” MYPBC3 patients and 144 “genotype-negative” patients. The average age of the cohort was 62 ± 16 years old, with 44% of patients of non-European ancestry. 47 (89%) of the pathogenic/likely pathogenic variants were truncating (i.e., frameshift, nonsense, or splice-site variants). These were homogenously distributed throughout the gene. Conversely, 5 of the 6 non-truncating missense variants were clustered together in exon 17. Of the 20 VUS, 18 were missense variants and 2 were in-frame insertion/deletions. A higher proportion of patients with VUS were of non-European ancestry compared to patients with benign variants/negative genetic testing (56% vs. 35%, p<0.01). Compared to genotype-negative patients, genotype-positive patients had more significant left ventricular hypertrophy (LVH) (septal wall thickness of 19 ± 6 mm vs. 17 ± 5 mm, p=0.01) and higher rates of ventricular arrhythmias (18% vs. 4%, p < 0.01). There was also a higher prevalence of late gadolinium enhancement detected on cardiac MRI, reflecting increased fibrosis, in genotype positive versus genotype negative patients (89% vs. 65%, p=0.04). Over a median follow-up time of 2.9 years, genotype-positive patients were significantly more likely to experience incident MACE compared to genotype-negative patients (hazard ratio: 1.65 [95% CI: 1.05-2.60], p=0.03). 



A secondary analysis compared patients with pathogenic/likely pathogenic variants in MYBPC3 (n=53) to patients with pathogenic/likely pathogenic variants in MYH7 (n = 28). Compared to MYH7 genotype-positive patients, MYBPC3genotype-positive patients had lower average ejection fraction (60 ± 11% vs. 66 ± 6%, p=0.01) and more significant LVH (septal wall thickness: 19 ± 6 mm vs. 15 ± 5 mm, p=0.01). They were also more likely to experience incident MACE compared to MYH7 genotype positive patients (hazard ratio 2.15 [95% CI: 1.08-4.30], p=0.03). 

Conclusion:
The majority of pathogenic variants identified in MYBPC3 in our cohort of patients with HCM were truncating variants. Patients with pathogenic/likely pathogenic variants in MYBPC3 tended to have a more severe phenotype at baseline compared to genotype-negative patients and MYH7 genotype-positive patients and were at higher risk for developing incident MACE during the follow-up period. 

 

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