Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy

Joshua K Meisner^#¹, Aaron Renberg^#², Eric D Smith³, Yao-Chang Tsan³, Brynn Elder³, Abbey Bullard³, Owen L Merritt³, Sean L Zheng⁴, Neal K Lakdawala⁵, Anjali T Owens⁶, Thomas D Ryan⁷, Erin M Miller⁷, Joseph W Rossano⁸, Kimberly Y Lin⁸, Brian L Claggett⁹, Euan A Ashley¹⁰, Michelle Michels¹¹, Rachel Lampert¹², John C Stendahl¹², Dominic Abrams¹³, Christopher Semsarian^{14

15}, Victoria N Parikh¹⁰, Matthew T Wheeler¹⁰, Jodie Ingles¹⁶, Iacopo Olivotto¹⁷, Sharlene M Day⁶, Sara Saberi³, Mark W Russell¹, Michael Previs¹⁸, Carolyn Y Ho⁵, James S Ware⁴, Adam S Helms³

Affiliations

¹ Department of Pediatrics, Division of Pediatric Cardiology (J.K.M., M.W.R.), University of Michigan, Ann Arbor.
² Cellular and Molecular Biology Program, Medical School (A.R.), University of Michigan, Ann Arbor.
³ Department of Internal Medicine, Division of Cardiovascular Medicine (E.D.S., Y.-C.T., B.E., A.B., O.L.M., S.S., A.S.H.), University of Michigan, Ann Arbor.
⁴ National Heart and Lung Institute and Medical Research Council Laboratory of Medical Sciences, Imperial College London, United Kingdom (S.L.Z., J.S.W.).
⁵ Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (N.K.L., C.Y.H.).
⁶ Penn Center for Inherited Cardiovascular Disease, Hospital of the University of Pennsylvania & Perelman School of Medicine at the University of Pennsylvania, Philadelphia (A.T.O., S.M.D.).
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Heart Institute, Cincinnati Children's Hospital Medical Center, OH (T.D.R., E.M.M.).
⁸ Department of Pediatrics, Children's Hospital of Philadelphia, PA (J.W.R., K.Y.L.).
⁹ Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA (B.L.C.).
¹⁰ Center for Inherited Cardiovascular Disease, Stanford Medicine, CA (E.A.A., V.N.P., M.T.W.).
¹¹ Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, The Netherlands (M.M.).
¹² Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT (R.L., J.C.S.).
¹³ Center for Cardiovascular Genetics, Boston Children's Hospital, MA (D.A.).
¹⁴ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, Sydney Medical School Faculty of Medicine and Health, University of Sydney, Australia (C.S.).
¹⁵ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (C.S.).
¹⁶ Genomics and Inherited Disease Program, Garvan Institute of Medical Research and University of New South Wales, Sydney, Australia (J.I.).
¹⁷ Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (I.O.).
¹⁸ Department of Molecular Physiology & Biophysics, University of Vermont, Burlington (M.P.).

^# Contributed equally.

PMID: 39633578
PMCID: PMC11913586 (available on 2026-03-18)
DOI: 10.1161/CIRCULATIONAHA.124.069398

Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy

Joshua K Meisner et al. Circulation. 2025.

. 2025 Mar 18;151(11):783-798.

doi: 10.1161/CIRCULATIONAHA.124.069398. Epub 2024 Dec 5.

Authors

Affiliations

¹ Department of Pediatrics, Division of Pediatric Cardiology (J.K.M., M.W.R.), University of Michigan, Ann Arbor.
² Cellular and Molecular Biology Program, Medical School (A.R.), University of Michigan, Ann Arbor.
³ Department of Internal Medicine, Division of Cardiovascular Medicine (E.D.S., Y.-C.T., B.E., A.B., O.L.M., S.S., A.S.H.), University of Michigan, Ann Arbor.
⁴ National Heart and Lung Institute and Medical Research Council Laboratory of Medical Sciences, Imperial College London, United Kingdom (S.L.Z., J.S.W.).
⁵ Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (N.K.L., C.Y.H.).
⁶ Penn Center for Inherited Cardiovascular Disease, Hospital of the University of Pennsylvania & Perelman School of Medicine at the University of Pennsylvania, Philadelphia (A.T.O., S.M.D.).
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Heart Institute, Cincinnati Children's Hospital Medical Center, OH (T.D.R., E.M.M.).
⁸ Department of Pediatrics, Children's Hospital of Philadelphia, PA (J.W.R., K.Y.L.).
⁹ Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA (B.L.C.).
¹⁰ Center for Inherited Cardiovascular Disease, Stanford Medicine, CA (E.A.A., V.N.P., M.T.W.).
¹¹ Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, The Netherlands (M.M.).
¹² Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT (R.L., J.C.S.).
¹³ Center for Cardiovascular Genetics, Boston Children's Hospital, MA (D.A.).
¹⁴ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, Sydney Medical School Faculty of Medicine and Health, University of Sydney, Australia (C.S.).
¹⁵ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (C.S.).
¹⁶ Genomics and Inherited Disease Program, Garvan Institute of Medical Research and University of New South Wales, Sydney, Australia (J.I.).
¹⁷ Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (I.O.).
¹⁸ Department of Molecular Physiology & Biophysics, University of Vermont, Burlington (M.P.).

^# Contributed equally.

PMID: 39633578
PMCID: PMC11913586 (available on 2026-03-18)
DOI: 10.1161/CIRCULATIONAHA.124.069398

Erratum in

Correction to: Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy.
Meisner JK, Renberg A, Smith ED, Tsan YC, Elder B, Bullard A, Merritt OL, Zheng SL, Lakdawala NK, Owens AT, Ryan TD, Miller EM, Rossano JW, Lin KY, Claggett BL, Ashley EA, Michels M, Lampert R, Stendahl JC, Abrams D, Semsarian C, Parikh VN, Wheeler MT, Ingles J, Olivotto I, Day SM, Saberi S, Russell MW, Previs M, Ho CY, Ware JS, Helms AS. Meisner JK, et al. Circulation. 2025 Mar 18;151(11):e762. doi: 10.1161/CIR.0000000000001318. Epub 2025 Mar 17. Circulation. 2025. PMID: 40096296 No abstract available.

Abstract

Background: Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity.

Methods: Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10^-5 in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2×) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data.

Results: Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; P<0.001). An intermediate functional impact was validated for 2 specific LowSVs-MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM.

Conclusions: 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.

Keywords: cardiomyopathies; cardiomyopathy, hypertrophic; genetic variation; induced pluripotent stem cells; penetrance; sarcomeres.

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Conflict of interest statement

N.K.L. is a consultant for Bristol Myers Squibb, Pfizer, Cytokinetics, Tenaya, and Sarepta and receives research funding from Pfizer. J.W.R. is a consultant for AskBio, American Regent, Bayer, Merck, Enzvyant, and Bristol Myers Squibb. D.A. is a consultant for Rocket Pharmaceuticals. V.N.P. receives research funding from BioMarin and consults for Nuevocor and Viz.ai. S.M.D. is a consultant for Tenaya and Lexeo. S.S. is a consultant for Bristol Myers Squibb and Cytokinetics. M.M. is a consultant for Bristol Myers Squibb and Cytokinetics. I.O. is a consultant for Bristol Myers Squibb, Amicus, Sanofi, Cytokinetics, Bayer, Tenaya, Rocket Pharma, and Lexeo. M.P. is a consultant for and receives research funding from Tenaya. C.Y.H. is a consultant for or receives research funding from Bristol Myers Squib, Pfizer, Cytokinetics, Tenaya, Biomarin, viz.AI, and Lexicon. J.S.W. has consulted for MyoKardia (now Bristol Myers Squibb), Foresite Labs, HealthLumen, and Pfizer. A.S.H. is a consultant or receives research funding from Tenaya and Lexeo. The other authors report no conflicts.

References

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Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy

Affiliations

Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous