Increased yield of genetic diagnoses in inherited heart diseases using expanded genome and RNA-splicing analyses
Year: 2025
Type: article
Abstract: PURPOSE: The Australian Genomics Cardiovascular Disorders Flagship investigated genome sequencing as a first-line genetic test in 600 individuals with cardiomyopathy, primary arrhythmia syndromes, or congenital heart disease. Analysis of disease-specific virtual gene panels achieved a genetic diagnosis in 38% of participants. We sought to increase genetic diagnosis yields by analyzing lesser-evidenced disease genes, the mitochondrial genome, and by functional analysis of predicted splice-altering variants. METHODS: Genome sequences of 520 participants with cardiomyopathy or primary arrhythmia syndromes were reanalyzed in 572 cardiac genes and the mitochondrial genome. Participants with congenital heart disease were excluded. Variants predicted in silico to disrupt splicing were assessed with blood RNA and minigenes. RESULTS: A new genetic diagnosis was achieved in 4% (19/520) of participants, including deep intronic and mitochondrial genome variants. Ten participants had diagnostic variants in lesser evidenced disease genes; 9 had splicing variant pathogenicity functionally validated. Eleven participants had a newly identified variant of uncertain significance with high suspicion of pathogenicity, warranting clinical review. Our data supported the gene-disease association of 1 new cardiomyopathy gene, TBX20. CONCLUSION: Identifying new gene-disease relationships, maintaining contemporary gene panels, and integrating functional studies to refine splicing variant classifications increase genetic diagnoses for cardiomyopathies and primary arrhythmia syndromes.
Source: Genetics in Medicine
Authors: Yuchen Chang, Emma M. Rath, Magdalena Soka, Emma S. Singer, Gunjan Trivedi, Charlotte Burns, Rachel Austin, Tiffany Boughtwood, Jaye S. Brown, Sarah Casauria, Belinda Chong, Jasmina Cvetkovska, Sally L. Dunwoodie, Sebastian Lunke, Tessa Mattiske, Julie McGaughran, Sarah-Jane Pantaleo, Michael C.J. Quinn, Chris Semsarian, Ivan Macciocca, Jodie Ingles, Diane Fatkin, Eleni Giannoulatou, Richard D. Bagnall, Adam Hill, Alejandro Metke, Alessandra Bray, Alison McLean, Alison Trainer, Amali Mallawaarachchi, Andreas Pflaumer, Andrew Davis, Andrew Kelly, Angela Overkov, Annabel Enriquez, Ansley Morrish, Ari E. Horton, Belinda Chong, Belinda Gray, Bernadette Hanna, Carla Smerdon, Carmen Herrera, Caroline Medi, Cassie Greer, Chai-Ann Ng, Charlotte Burns, Chirag Patel, Chris Barnett, Chris Semsarian, David Elliott, David Mowat, David Winlaw, Debjani Das, Denise Howting, Denisse Garza, Di Milnes, Diane Fatkin, Dimithu Alankarage, Dominica Zentner, Dotti Tang, Edwin Kirk, Eleni Giannoulatou, Ellenore Martin, Emma M. Rath, Emma S. Singer, Eric Haan, Evanthia O. Madelli, Felicity Collins, Fiona Cunningham, Gavin Chapman, Gemma Correnti, Georgie Hollingsworth, Georgina Hollway, Gillian M. Blue, Giulia Valente, Gunjan Trivedi, Hariharan Raju, Heather Chalinor, Helen Mountain, Isabella Sherburn, Ivan Macciocca, Jacob Mathew, James McNamara, Jamie Vandenberg, Janette Hayward, Janine Smith, Jason Davis, Jaye Brown, Jessica Taylor, Jim Morwood, Jitendra Vohra, Joanne Isbister, Jodie Ingles, John J. Atherton, Jonathan Rogers, Jonathon Lipton, Jordan Thorpe, Julia Dobbins, Julia Mansour, Julie McGaughran, Karin van Spaendonck-Zwarts, Kathryn Waddel-Smith, Kathy Cox, Kathy Wu, Keri Finlay, Kirsten Boggs, Kunal Verma, Laura Gongolidis, Laura Yeates, Lesley Ades, Leslie Burnett, Linda Wornham, Lisa Worgan, Magdalena Soka, Marie-Jo Brion, Mark Perrin, Mark Ryan, Mary-Clare Sherlock, Mathew Wallis, Mathilda Haas, Matilda Jackson, Matthew Perry, Matthew Regan, Meredith Wilson, Michael Bogwitz, Michael C.J. Quinn, Michael Milward, Michel Tchan, Michelle Cao, Michelle de Silva, Miranda Vidgen, Miriam Fine, Mohammad Al-Shinnag, Monique Ohanian, Morgan Almog, Natalie Nowak, Nathan Dwyer, Nicholas Pachter, Nicola Den Elzen, Nicola K. Poplawski, Nicole Schonrock, Noelia Nunez Martinez, Paul De Fazio, Paul James, Paul MacIntyre, Paul Scuffham, Peta Phillips, Preeti Punni, Rachel Austin, Rachel Pope-Couston, Raymond Sy, Renee Johnson, Renee Smyth, Richard D. Bagnall, Richard Harvey, Rob Bryson Richardson, Robert G. Weintraub, Sally L. Dunwoodie, Sarah Casauria, Sarah King-Smith, Sarah Kummerfeld, Sarah Sandaradura, Sarah-Jane Pantaleo, Sebastian Lunke, Shelby Taylor, Simon Bodek, Sinead O’Sullivan, Sophie Devery, Stefanie Elbracht-Leong, Sulekha Rajagopalan, Tessa Mattiske, Theosodia Charitou, Thuan Phuong, Tiffany Boughtwood, Timo Lassman, Tina Thompson, Vanessa Fear, Will Carr, Yuchen Chang, Zornitza Stark
Institutions: The University of Sydney, Centenary Institute, Victor Chang Cardiac Research Institute, UNSW Sydney, Royal Prince Alfred Hospital, Royal Brisbane and Women's Hospital, Australian Genomics Health Alliance, Murdoch Children's Research Institute, Victorian Clinical Genetics Services, The University of Queensland, Royal Children's Hospital, The University of Melbourne, Garvan Institute of Medical Research, St Vincent's Hospital Sydney
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,110
Awards: G2956611489, Preparing Australia for Genomic Medicine: A proposal by the Australian Genomics Health Alliance, Improving the genetic diagnosis of cardiovascular disease, The Australian Genomics Cardiovascular Genetic Disorders Flagship, Translating Genomics into Improved Care of Inherited Heart Disease and Sudden Death Families
OpenAlex ID: W4415653998