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Cited by 7

The DOI matches its Crossref record.

A rare splice-site variant in TNNT2: the need for ancestral diversity in genomic reference data sets

Butters, Alexandra, Thomson, Kate, Harrington, Franki, Henden, Natasha, McGuire, Karen, Byrne, Alicia B, Bryen, Samantha, McGurk, Kathryn A, Leask, Megan, Ackerman, Michael J, Atherton, John, Bos, Johan M, Caleshu, Colleen, Day, Sharlene M, Dunn, Kyla, Hayes, Ian, Juang, Jimmy, McGaughran, Julie, Nowak, Natalie, Parikh, Victoria N, Ronan, Anne, Semsarian, Christopher, Tardiff, Jil C, Tiemensma, Marianne, Merriman, Tony R, Ware, James S, Skinner, Jonathan R, MacArthur, Daniel G, Siggs, Owen M, Bagnall, Richard D, Ingles, Jodie·2025·European Heart Journal
DOI 10.1093/eurheartj/ehaf001
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Abstract

Inherited cardiomyopathies, including hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathies affect ∼1 in 200–500 in the population. Genetic testing is standard practice and typically identifies causal variants in approximately half of cases. Cardiac troponin T (TNNT2) is an integral protein in the cardiac sarcomere and is definitively associated with HCM and DCM. The underrepresentation of diverse ancestries in genomic data sets complicates variant interpretation, especially for non-European populations, where genetic testing has a lower diagnostic yield.1 Among rare monogenic diseases, allele frequency in population reference databases contributes to understanding whether a variant is potentially pathogenic. While global efforts like gnomAD v4.0 have improved ancestral diversity, individuals with Oceanian ancestry, i.e. a geographical region on the Pacific Ocean comprising Australasia, Melanesia, Micronesia, and Polynesia, remain underrepresented. We report a variant, TNNT2; NM_001001430.3: c.571-1G>A (rs483352835), in two unrelated probands with Oceanian ancestry and cardiac phenotypes, seen at a specialized genetic heart disease clinic in Sydney, Australia, who consented to research-based whole-genome sequencing (RPA Hospital Sydney Local Health District Human Research Ethics Committee X15-0089). Variant classification was performed by research genetic counsellors using the MYH7-modified ACMG/AMP criteria and discussed at a dedicated cardiac genetic mul…

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Research works printed but not linked: 10

  1. Petrovski, 2016, Unequal representation of genetic variation across ancestry groups creates healthcare inequality in the application of precision medicine, Genome Biol, 17, 157, 10.1186/s13059-016-1016-y · DOI · Paper page
  2. O’Leary, 2016, Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation, Nucleic Acids Res, 44, D733, 10.1093/nar/gkv1189 · DOI · Paper page
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  4. Wall, 2019, The GenomeAsia 100K project enables genetic discoveries across Asia, Nature, 576, 106, 10.1038/s41586-019-1793-z · DOI
  5. Feng, 2022, Taiwan Biobank: a rich biomedical research database of the Taiwanese population, Cell Genom, 2, 100197, 10.1016/j.xgen.2022.100197 · DOI
  6. Parks, 2017, Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania, Nat Commun, 8, 14946, 10.1038/ncomms14946 · DOI
  7. Emde, 2021, Mid-pass whole genome sequencing enables biomedical genetic studies of diverse populations, BMC Genomics, 22, 666, 10.1186/s12864-021-07949-9 · DOI
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Metadata

Authors
Butters, A., Thomson, K., Harrington, F., Henden, N., McGuire, K., Byrne, A. B., Bryen, S., McGurk, K. A., Leask, M., Ackerman, M. J., Atherton, J., Bos, J. M., Caleshu, C., Day, S. M., Dunn, K., Hayes, I., Juang, J., McGaughran, J., Nowak, N., Parikh, V. N., Ronan, A., Semsarian, C., Tardiff, J. C., Tiemensma, M., Merriman, T. R., Ware, J. S., Skinner, J. R., MacArthur, D. G., Siggs, O. M., Bagnall, R. D., & Ingles, J.
Affiliations
  • Genomics and Inherited Disease Program, Garvan Institute of Medical Research and University of New South Wales , 384 Victoria Street, Darlinghurst, Sydney, NSW 2010 ,
  • Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust , Oxford ,
  • Genetic Health Service New Zealand, Northern Hub Auckland Hospital , Auckland ,
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MA ,
  • Centre for Population Genomics, Garvan Institute of Medical Research and UNSW , Sydney ,
  • University of Otago , Dunedin ,
  • Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic , Rochester, MN ,
  • Department of Cardiology, Royal Brisbane Women’s Hospital , Brisbane ,
  • Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine ,
  • Division of Cardiovascular Medicine, University of Pennsylvania , Philadelphia, PA ,
  • Cardiovascular Center and Division of Cardiology, National Taiwan University Hospital , Taipei ,
  • Genetic Health Queensland , Brisbane ,
  • Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney , Sydney ,
  • Newcastle Medical Genetics, University of Newcastle , NSW ,
  • Faculty of Medicine and Health, The University of Sydney , Sydney ,
  • Department of Biomedical Engineering, University of Arizona , Tucson, AZ ,
  • Forensic Pathology Unit, Royal Darwin Hospital , Darwin ,
  • The Cardiac Inherited Disease Group , Auckland ,
ORCID
Venue
European Heart Journal
Publisher
Oxford University Press (OUP)
Published
2025-03-05
Volume
46
Issue
15
Pages
1446-1449
ISSN
  • 0195-668X
  • 1522-9645
DOI
10.1093/eurheartj/ehaf001
Cited by
7
References
0
Language
en
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Funders
  • National Heart Foundation of Australia Future Leader Fellowship (#106732)
  • New South Wales Health Cardiovascular Disease Senior Scientist Grant
  • National Health and Medical Research Council (#2016822)
  • New South Wales Health Cardiovascular Disease Clinician Scientist Grant
  • New South Wales (NSW) Health Cardiovascular Research Capacity Program
  • British Heart Foundation (PG/14/26/30509)
  • Medical Research Declarations Form Council UK (G1100449)
  • British Medical Association (FS/IPBSRF/22/27059, RE/18/4/34215)
  • NIHR
  • Imperial College Biomedical Research Centre
  • Sir Jules Thorn Charitable Trust (21JTA)
  • Medical Research Council

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CoChat. (2026). Citation check: A rare splice-site variant in TNNT2: the need for ancestral diversity in genomic reference data sets. https://app.cochat.ai/papers/10.1093/eurheartj/ehaf001
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Butters, A., Thomson, K., Harrington, F., Henden, N., McGuire, K., Byrne, A. B., Bryen, S., McGurk, K. A., Leask, M., Ackerman, M. J., Atherton, J., Bos, J. M., Caleshu, C., Day, S. M., Dunn, K., Hayes, I., Juang, J., McGaughran, J., Nowak, N., . . . Ingles, J. (2025). A rare splice-site variant in TNNT2: the need for ancestral diversity in genomic reference data sets. European Heart Journal. https://doi.org/10.1093/eurheartj/ehaf001