Heart failure & cardiomyopathiesDiagnostic or prognostic study
Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy
- Genetic association study
- registry-based
- functional validation in iPSC-derived cardiomyocytes
- UK Biobank CMR analysis
Authors' conclusion
This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.
Study context
- Population
- Patients with hypertrophic cardiomyopathy (HCM) in the Sarcomeric Human Cardiomyopathy Registry (SHaRe); UK Biobank general population1,159 unique sarcomere variants
- Participants
- 6,045 patients
- Comparison
- LowSVs vs single pathogenic sarcomere variant
Performance
As reported in the abstract
HCM enrichment and composite adverse events with LowSVs
Estimate (95% CI)P value
LowSVs vs gnomADenrichment in HCM
aggregate OR 14.9(12.5–17.9)
LowSV + pathogenic sarcomere variantcomposite adverse events; vs single pathogenic sarcomere variant HR 2.0 (95% CI, 1.8-2.2)
HR 5.4(3.0–9.8)
P < 0.001- LowSVs collectively common in general population
- 1:350
Further findings
Functional impact in iPSC-derived cardiomyocytes
- Intermediate functional impact validated for MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics)
- 2
HCM-adjacent traits on CMR, general population (UK Biobank)
- LowSVs significantly associated with HCM-adjacent traits without overt HCM
- 5 of 12
Original publication
Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy. Circulation. Published 5 December 2024. doi:10.1161/circulationaha.124.069398
Summarised from the published abstract; every number is checked against it