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[Preprint]. 2024 Jul 31:2024.07.29.24311195.

doi: 10.1101/2024.07.29.24311195.

ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy

Sophie Hespe¹, Amber Waddell², Babken Asatryan³, Emma Owens², Courtney Thaxton², Mhy-Lanie Adduru⁴, Kailyn Anderson⁵, Emily E Brown⁶, Lily Hoffman-Andrews⁷, Elizabeth Jordan⁸, Katherine Josephs⁹, Megan Mayers², Stacey Peters¹⁰, Fergus Stafford¹, Richard D Bagnall^{11

12}, Lucas Bronicki^{13

14}, Bert Callewaert^{15

16}, C Anwar A Chahal¹⁷, Cynthia A James⁶, Olga Jarinova^{14

18}, Andrew P Landstrom¹⁹, Elizabeth M McNally²⁰, Brittney Murray⁶, Laura Muiño-Mosquera^{16

21}, Victoria Parikh²², Chloe Reuter²², Roddy Walsh²³, Bess Wayburn²⁴, James S Ware^{9

25

26}, Jodie Ingles^{1

27}

Affiliations

¹ Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia.
² Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Predictiv Care, San Francisco, CA, USA.
⁵ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
⁶ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁷ Division of Cardiovascular Medicine, Department of Medicine, Center for Inherited Cardiovascular Disease, Perelman School of Medicine at the University of Pennsylvania, Perelman Center for Advanced Medicine, Philadelphia, PA, USA.
⁸ Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus, OH, USA.
⁹ National Heart and Lung Institute and MRC Laboratory of Medical Science, Imperial College London, London, UK.
¹⁰ Department of Cardiology and Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia.
¹¹ Bioinformatics and Molecular Genetics at Centenary Institute, University of Sydney, Sydney, Australia.
¹² Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
¹³ Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.
¹⁴ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
¹⁵ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
¹⁶ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
¹⁷ Center for Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, Pennsylvania, USA; Mayo Clinic, Rochester, MN, USA; Barts Heart Centre, London, UK, William Harvey Research Institute, Queen Mary University of London, London, UK.
¹⁸ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
¹⁹ Department of Pediatrics and Cell Biology, Duke University School of Medicine, Durham, NC, USA.
²⁰ Center for Genetic Medicine, Dept of Medicine (Cardiology), Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
²¹ Division of Pediatric Cardiology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.
²² Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²³ Amsterdam University Medical Centre, University of Amsterdam, Heart Center, Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
²⁴ Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
²⁵ Hammersmith Hospital, Imperial College Healthcare NHS Foundation Trust, London, UK.
²⁶ Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK.
²⁷ School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Australia.

PMID: 39132495
PMCID: PMC11312670
DOI: 10.1101/2024.07.29.24311195

ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy

Sophie Hespe et al. medRxiv. 2024.

[Preprint]. 2024 Jul 31:2024.07.29.24311195.

doi: 10.1101/2024.07.29.24311195.

Authors

Affiliations

¹ Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia.
² Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Predictiv Care, San Francisco, CA, USA.
⁵ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
⁶ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁷ Division of Cardiovascular Medicine, Department of Medicine, Center for Inherited Cardiovascular Disease, Perelman School of Medicine at the University of Pennsylvania, Perelman Center for Advanced Medicine, Philadelphia, PA, USA.
⁸ Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus, OH, USA.
⁹ National Heart and Lung Institute and MRC Laboratory of Medical Science, Imperial College London, London, UK.
¹⁰ Department of Cardiology and Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia.
¹¹ Bioinformatics and Molecular Genetics at Centenary Institute, University of Sydney, Sydney, Australia.
¹² Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
¹³ Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.
¹⁴ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
¹⁵ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
¹⁶ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
¹⁷ Center for Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, Pennsylvania, USA; Mayo Clinic, Rochester, MN, USA; Barts Heart Centre, London, UK, William Harvey Research Institute, Queen Mary University of London, London, UK.
¹⁸ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
¹⁹ Department of Pediatrics and Cell Biology, Duke University School of Medicine, Durham, NC, USA.
²⁰ Center for Genetic Medicine, Dept of Medicine (Cardiology), Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
²¹ Division of Pediatric Cardiology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.
²² Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²³ Amsterdam University Medical Centre, University of Amsterdam, Heart Center, Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
²⁴ Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
²⁵ Hammersmith Hospital, Imperial College Healthcare NHS Foundation Trust, London, UK.
²⁶ Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK.
²⁷ School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Australia.

PMID: 39132495
PMCID: PMC11312670
DOI: 10.1101/2024.07.29.24311195

Update in

Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel.
Hespe S, Waddell A, Asatryan B, Owens E, Thaxton C, Adduru ML, Anderson K, Brown EE, Hoffman-Andrews L, Jordan E, Josephs K, Mayers M, Peters S, Stafford F, Bagnall RD, Bronicki L, Callewaert B, Chahal CAA, James CA, Jarinova O, Landstrom AP, McNally EM, Murray B, Muiño-Mosquera L, Parikh V, Reuter C, Walsh R, Wayburn B, Ware JS, Ingles J. Hespe S, et al. J Am Coll Cardiol. 2025 Feb 25;85(7):727-740. doi: 10.1016/j.jacc.2024.12.010. J Am Coll Cardiol. 2025. PMID: 39971408 Free PMC article.

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Here we report work by the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes.

Methods: The ClinGen systematic gene curation framework was used to re-classify the gene-disease relationships for HCM and related syndromic entities involving left ventricular hypertrophy. Genes previously curated were included if their classification was not definitive, and if the time since curation was >2-3 years. New genes with literature assertions for HCM were included for initial evaluation. Existing genes were curated for new inheritance patterns where evidence existed. Curations were presented on twice monthly calls, with the HCVD-GCEP composed of 29 individuals from 21 institutions across 6 countries.

Results: Thirty-one genes were re-curated and an additional 5 new potential HCM-associated genes were curated. Among the re-curated genes, 17 (55%) genes changed classification: 1 limited and 4 disputed (from no known disease relationship), 9 disputed (from limited), and 3 definitive (from moderate). Among these, 3 (10%) genes had a clinically relevant upgrade, including TNNC1, a 9th sarcomere gene with definitive HCM association. With new evidence, two genes were curated for multiple inheritance patterns (TRIM63, disputed for autosomal dominant but moderate for autosomal recessive; ALPK3, strong for autosomal dominant and definitive for recessive). CSRP3 was curated for a semi-dominant mode of inheritance (definitive). Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes. Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive).

Conclusions: We report 29 genes with definitive, strong or moderate evidence of causation for HCM or isolated LVH, including sarcomere, sarcomere-associated and syndromic conditions.

PubMed Disclaimer

Conflict of interest statement

COMPETING INTERESTS EMM is an advisor to Amgen, Cytokinetics, PepGen, and Tenaya, and is a founder of Ikaika Therapeutics. JW has consulted for MyoKardia, Inc., Pfizer, Foresite Labs, Health Lumen, and Tenaya Therapeutics, and receives research support from Bristol Myers-Squibb. JI receives research grant support from Bristol Myers Squibb unrelated to this work. All other authors declare no competing interests.

Figures

**FIGURE 1:. Comparison of original and updated classifications.**
Hypertrophic cardiomyopathy (HCM) gene-disease classifications showing the genetic and experimental evidence point totals from the original curation compared to the re-curation. Including 17 changes of classification; 3 upgraded from moderate to definitive, 1 upgraded from no evidence to limited, and 13 downgraded to disputed. There are 7 new curations; 5 new genes and 2 existing genes with new modes of inheritance.

**FIGURE 2:. Updated list of genes with moderate, strong or definitive hypertrophic cardiomyopathy (HCM) association.**
We highlight the genetic architecture of HCM, or genocopies causing left ventricular hypertrophy (innermost circle), spanning numerous gene ontologies (middle circle). Genes classified as definitive or strong evidence are emphasized in bold.

**FIGURE 3:**
Overview of genetic sub-types of hypertrophic cardiomyopathy and associated genes with moderate, strong or definitive evidence.

See this image and copyright information in PMC

References

1. Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM, Dearani J, Epps KC, Evanovich L, Ferrari VA, Joglar JA, Khan SS, Kim JK, Kittleson MM, Krittanawong C, Martinez MW, Mital S, Naidu S, Saberi S, Semsarian C, Times S, Waldman CB. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2024;e1239–e1311. - PubMed
1. Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, Bezzina CR, Biagini E, Blom NA, de Boer RA, De Winter T, Elliott PM, Flather M, Garcia-Pavia P, Haugaa KH, Ingles J, Jurcut RO, Klaassen S, Limongelli G, Loeys B, Mogensen J, Olivotto I, Pantazis A, Sharma S, Van Tintelen JP, Ware JS, Kaski JP, ESC Scientific Document Group. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;ehad194. - PubMed
1. McGurk KA, Zhang X, Theotokis P, Thomson K, Harper A, Buchan RJ, Mazaika E, Ormondroyd E, Wright WT, Macaya D, Pua CJ, Funke B, MacArthur DG, Prasad SK, Cook SA, Allouba M, Aguib Y, Yacoub MH, O’Regan DP, Barton PJR, Watkins H, Bottolo L, Ware JS. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023;110:1482–1495. - PMC - PubMed
1. Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Document Reviewers, Aiba T, Bollmann A, Choi J-I, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn AD, MacIntyre C, Mackall JA, Mont L, Napolitano C, Ochoa JP, Peichl P, Pereira AC, Schwartz PJ, Skinner J, Stellbrink C, Tfelt-Hansen J, Deneke T. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases. Heart Rhythm. 2022;19:e1–e60. - PubMed
1. Tuohy CV, Kaul S, Song HK, Nazer B, Heitner SB. Hypertrophic cardiomyopathy: the future of treatment. Eur J Heart Fail. 2020;22:228–240. - PubMed

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This is a preprint.

ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy

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ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy

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