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TBX20 loss-of-function variants in families with left ventricular non-compaction cardiomyopathy
  1. Yuchen Chang1,2,
  2. Julie Wacker3,
  3. Jodie Ingles2,4,5,6,
  4. Ivan Macciocca5,7,
  5. Ingrid King5,
  6. The Australian Genomics Cardiovascular Disorders Flagship1,2,
  7. Christopher Semsarian2,6,8,
  8. Julie McGaughran9,10,
  9. Robert G Weintraub3,5,
  10. Richard D Bagnall1,2
  1. 1Bioinformatics and Molecular Genetics at Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia
  2. 2Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
  3. 3Department of Cardiology, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia
  4. 4Centre for Population Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
  5. 5Clinical Sciences, Murdoch Children's Research Institute, Parkville, Victoria, Australia
  6. 6Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
  7. 7Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia
  8. 8Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia
  9. 9Genetic Health QLD, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
  10. 10Faculty of Medicine, The University of Queensland, Saint Lucia, Queensland, Australia
  1. Correspondence to Dr Richard D Bagnall, Bioinformatics and Molecular Genetics, Centenary Institute, Newtown, New South Wales, Australia; r.bagnall{at}


TBX20 encodes a cardiac transcription factor that is associated with atrial septal defects. Recent studies implicate loss-of-function TBX20 variants with left ventricular non-compaction cardiomyopathy (LVNC), although clinical and genetic data in families are limited. We report four families with TBX20 loss-of-function variants that segregate with LVNC. Genetic testing using genome or exome sequencing was performed in index cases, variants were validated with Sanger sequencing, and cascade genetic testing was performed in family members. A multi-exon deletion, small deletion, essential splice site variant and nonsense variant in TBX20 were found in four families. The index cases in two families were symptomatic children with identical congenital heart diseases and LVNC who developed different cardiomyopathy phenotypes with one developing heart failure requiring transplantation. In another family, the child index case had LVNC and congestive heart failure requiring heart transplantation. In the fourth family, the index case was a symptomatic adult with LVNC. In all families, the variants segregated in relatives with isolated LVNC, or with congenital heart disease or cardiomyopathy. Family members displayed a clinical spectrum from asymptomatic to severe presentations including heart failure. Our data strengthen TBX20 loss-of-function variants as a rare cause of LVNC and support TBX20 inclusion in genetic testing of LVNC.

  • cardiomyopathies
  • heart defects, congenital
  • loss of function mutation
  • genetics
  • genetics, medical

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  • Collaborators The Australian Genomics Cardiovascular Disorders Flagship. Alison Trainer, Andreas Pflaumer, Andrew Davis, Andrew Kelly, Andy Ng (Chai), Angela Overkov, Ansley Morrish, Belinda Gray, Bernadette Hanna, Carla Smerdon, Caroline Medi, Charlotte Burns, Chirag Patel, Chris Barnett, Chris Semsarian, David Elliott, David Winlaw, Debjani Das, Denisse Garza, Di Milnes, Diane Fatkin, Dimithu, Dominica Zentner, Ari Horton, Kunal Verma, Matthew Regan, Edwin Kirk, Eleni Giannoulatou, Elleanor Martin, Emma Rath, Emma Singer, Eric Haan, Fiona Cunningham, Gavin Chapman, Gemma Correnti, Gillian Blue, Giulia, Gunjan Trivedi, Heather Chalinor, Helen Mountain, Ivan Macciocca, James McNamara, James Morwood, Jamie Vandenberg, Janette Hayward, Janine Smith, Jaye Brown, Jitendra Vohra, Jodie Ingles, John Atherton, Jonathan Rogers, Jonathon Lipton, Julia Dobbins, Julia Mansour, Julie McGaughran, Karin van Spaendonck-Zwarts, Kathy Cox, Kathy Wu, Kirsten Boggs, Laura G, Laura Yeates, Lesley Ades, Linda Wornham, Magdalena Soka, Mark Perrin, Mark Ryan, Mary-Clare Sherlock, Mathew Wallis, Matilda Jackson, Meredith Wilson, Michael Feitz, Michael Quinn, Michel Tchan, Michelle Cao, Michelle de Silva, Miriam Fine, Mohammad Al-Shinnag, Natalie Nowak, Nathan Dwyer, Nicholas Pachter, Nicola Poplawski, Paul James, Paul MacIntyre, Preeti Punni, Rachel Austin, Raymond Sy, Renee Johnson, Renee Smyth, Richard Bagnall, Richard Harvey, Rob Bryson Richardson, Robert Weintraub, Sally Dunwoodie, Sarah Casauria, Simon Bodek, Sinead O’Sullivan, Sophie Devery, Sulekha Rajagopalan, Tessa Mattiske, Timo Lassman, Tina Thompson, Tiffany Boughtwood, Vana Madelli, Vanessa Fear, Yuchen Chang.

  • Contributors Patient recruitment: JW, JI, IM, IK, CS, JMcG, RGW,

    The Australian Genomics Cardiovascular Disorders Flagship (AGCDF); clinical evaluation: JM, RGW; data analysis and interpretation: YC, JI, AGCDF, IM, CS, JM, RB; writing: YC, RB.

  • Funding RB is the recipient of an NSW Health Cardiovascular Disease Senior Scientist Grant. CS is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (#2016822) and an NSW Health Cardiovascular Disease Clinician Scientist Grant. JI is the recipient of a Heart Foundation Future Leader Fellowship (106732). The Australian Genomics Cardiovascular Genetic Disorders Flagship was funded by the Medical Research Future Fund (EPCD000028). Australian Genomics is funded by The National Health and Medical Research Council (GNTIER 1113531 and GNTIER 2000001).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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