. 2024 Mar 25:2:101842.

doi: 10.1016/j.gimo.2024.101842. eCollection 2024.

A multitiered analysis platform for genome sequencing: Design and initial findings of the Australian Genomics Cardiovascular Disorders Flagship

Rachel Austin^{1

2}, Jaye S Brown^{1

3

4}, Sarah Casauria^{1

5}, Evanthia O Madelli^{1

5}, Tessa Mattiske¹, Tiffany Boughtwood^{1

5}, Alejandro Metke⁶, Andrew Davis^{5

7

8}, Ari E Horton^{9

10

11}, David Winlaw¹², Debjani Das¹³, Magdalena Soka¹³, Eleni Giannoulatou^{13

14}, Emma M Rath^{13

14}, Eric Haan¹⁵, Gillian M Blue^{16

17}, Jitendra Vohra^{8

10}, John J Atherton^{18

19}, Karin van Spaendonck-Zwarts², Kathy Cox²⁰, Leslie Burnett^{4

21

22}, Mathew Wallis^{23

24}, Matilda Haas^{1

5}, Michael C J Quinn^{1

2}, Nicholas Pachter^{25

26}, Nicola K Poplawski^{27

28}, Zornitza Stark^{1

29}, Richard D Bagnall³, Robert G Weintraub^{5

7

8}, Sarah-Jane Pantaleo²⁹, Sebastian Lunke²⁹, Paul De Fazio²⁹, Tina Thompson^{8

10}, Paul James¹⁰, Yuchen Chang³, Diane Fatkin^{13

14

30}, Ivan Macciocca^{7

8

29}, Jodie Ingles^{4

31}, Sally L Dunwoodie^{13

14}, Chris Semsarian³, Julie McGaughran^{2

18}; Australian Genomics Cardiovascular Disorders Flagship

Collaborators, Affiliations

Collaborators

Australian Genomics Cardiovascular Disorders Flagship:
Lesley Ades, Annabel Enriquez, Alison McLean, Renee Smyth, Dimithu Alankarage, Diane Fatkin, James McNamara, Magdalena Soka, Morgan Almog, Vanessa Fear, Caroline Medi, Zornitza Stark, Mohammad Al-Shinnag, Miriam Fine, Alejandro Metke, Raymond Sy, John J Atherton, Keri Finlay, Di Milnes, Dotti Tang, Rachel Austin, Denisse Garza, Michael Milward, Jessica Taylor, Richard D Bagnall, Eleni Giannoulatou, Ansley Morrish, Shelby Taylor, Chris Barnett, Laura Gongolidis, Jim Morwood, Michel Tchan, Gillian M Blue, Belinda Gray, Helen Mountain, Tina Thompson, Simon Bodek, Cassie Greer, David Mowat, Jordan Thorpe, Kirsten Boggs, Eric Haan, Chai-Ann Ng, Alison Trainer, Michael Bogwitz, Mathilda Haas, Natalie Nowak, Gunjan Trivedi, Tiffany Boughtwood, Bernadette Hanna, Noelia Nunez Martinez, Giulia Valente, Alessandra Bray, Richard Harvey, Monique Ohanian, Karin van Spaendonck-Zwarts, Marie-Jo Brion, Janette Hayward, Sinead O'Sullivan, Jamie Vandenberg, Jaye Brown, Carmen Herrera, Angela Overkov, Kunal Verma, Rob Bryson Richardson, Adam Hill, Nicholas Pachter, Miranda Vidgen, Leslie Burnett, Georgie Hollingsworth, Chirag Patel, Jitendra Vohra, Charlotte Burns, Georgina Hollway, Mark Perrin, Kathryn Waddel-Smith, Michelle Cao, Ari E Horton, Matthew Perry, Mathew Wallis, Will Carr, Denise Howting, Andreas Pflaumer, Robert G Weintraub, Sarah Casauria, Jodie Ingles, Peta Phillips, Meredith Wilson, Heather Chalinor, Joanne Isbister, Thuan Phuong, David Winlaw, Yuchen Chang, Matilda Jackson, Rachel Pope-Couston, Lisa Worgan, Gavin Chapman, Paul James, Nicola K Poplawski, Linda Wornham, Theosodia Charitou, Sarah Jane-Pantaleo, Preeti Punni, Kathy Wu, Belinda Chong, Renee Johnson, Michael Cj Quinn, Laura Yeates, Felicity Collins, Andrew Kelly, Michael Quinn, Dominica Zentner, Gemma Correnti, Sarah King-Smith, Sulekha Rajagopalan, Kathy Cox, Edwin Kirk, Hariharan Raju, Fiona Cunningham, Sarah Kummerfeld, Emma M Rath, Debjani Das, Timo Lassman, Matthew Regan, Jason Davis, Jonathon Lipton, Jonathan Rogers, Andrew Davis, Sebastian Lunke, Mark Ryan, Paul De Fazio, Ivan Macciocca, Sarah Sandaradura, Michelle de Silva, Paul MacIntyre, Nicole Schonrock, Nicola Den Elzen, Evanthia O Madelli, Paul Scuffham, Sophie Devery, Amali Mallawaarachchi, Chris Semsarian, Julia Dobbins, Julia Mansour, Isabella Sherburn, Sally L Dunwoodie, Ellenore Martin, Mary-Clare Sherlock, Nathan Dwyer, Jacob Mathew, Emma Singer, Stefanie Elbracht-Leong, Tessa Mattiske, Carla Smerdon, David Elliott, Julie McGaughran, Janine Smith

Affiliations

¹ Australian Genomics, Parkville, VIC, Australia.
² Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
³ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia.
⁴ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
⁵ Murdoch Children's Research Institute, Parkville, VIC, Australia.
⁶ The Australian e-Health Research Centre, CSIRO, Herston, QLD, Australia.
⁷ Royal Children's Hospital, Parkville, VIC, Australia.
⁸ The University of Melbourne, Parkville, VIC, Australia.
⁹ Monash Children's Hospital and Monash Heart, Monash Health, Clayton, VIC, Australia.
¹⁰ Department of Genomic Medicine, The Royal Melbourne Hospital Parkville, VIC, Australia.
¹¹ Victorian Heart Institute, Monash University, Clayton, VIC, Australia.
¹² Sydney Children's Hospital Network, Westmead, NSW, Australia.
¹³ Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
¹⁴ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia.
¹⁵ SA clinical Genetics Service, Women's and Children's Hospital, North Adelaide, SA, Australia.
¹⁶ Heart Centre for Children, Sydney Children's Hospital Network, Sydney, NSW, Australia.
¹⁷ Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
¹⁸ School of Medicine, The University of Queensland, St Lucia, QLD, Australia.
¹⁹ Cardiology Department, Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
²⁰ SA Pathology, Adelaide, SA, Australia.
²¹ School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Healthcare Clinical Campus, UNSW Sydney, Darlinghurst, NSW, Australia.
²² Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia.
²³ Tasmanian Clinical Genetics Service, Tasmanian Health Service, Hobart, TAS, Australia.
²⁴ School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
²⁵ King Edward Memorial Hospital, Subiaco, WA, Australia.
²⁶ Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.
²⁷ Discipline of Paediatrics, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
²⁸ Adult Genetic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
²⁹ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.
³⁰ Cardiology Department, St Vincent's Hospital, Darlinghurst, NSW, Australia.
³¹ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

PMID: 39669597
PMCID: PMC11613726
DOI: 10.1016/j.gimo.2024.101842

A multitiered analysis platform for genome sequencing: Design and initial findings of the Australian Genomics Cardiovascular Disorders Flagship

Rachel Austin et al. Genet Med Open. 2024.

. 2024 Mar 25:2:101842.

doi: 10.1016/j.gimo.2024.101842. eCollection 2024.

Authors

Collaborators

Australian Genomics Cardiovascular Disorders Flagship:
Lesley Ades, Annabel Enriquez, Alison McLean, Renee Smyth, Dimithu Alankarage, Diane Fatkin, James McNamara, Magdalena Soka, Morgan Almog, Vanessa Fear, Caroline Medi, Zornitza Stark, Mohammad Al-Shinnag, Miriam Fine, Alejandro Metke, Raymond Sy, John J Atherton, Keri Finlay, Di Milnes, Dotti Tang, Rachel Austin, Denisse Garza, Michael Milward, Jessica Taylor, Richard D Bagnall, Eleni Giannoulatou, Ansley Morrish, Shelby Taylor, Chris Barnett, Laura Gongolidis, Jim Morwood, Michel Tchan, Gillian M Blue, Belinda Gray, Helen Mountain, Tina Thompson, Simon Bodek, Cassie Greer, David Mowat, Jordan Thorpe, Kirsten Boggs, Eric Haan, Chai-Ann Ng, Alison Trainer, Michael Bogwitz, Mathilda Haas, Natalie Nowak, Gunjan Trivedi, Tiffany Boughtwood, Bernadette Hanna, Noelia Nunez Martinez, Giulia Valente, Alessandra Bray, Richard Harvey, Monique Ohanian, Karin van Spaendonck-Zwarts, Marie-Jo Brion, Janette Hayward, Sinead O'Sullivan, Jamie Vandenberg, Jaye Brown, Carmen Herrera, Angela Overkov, Kunal Verma, Rob Bryson Richardson, Adam Hill, Nicholas Pachter, Miranda Vidgen, Leslie Burnett, Georgie Hollingsworth, Chirag Patel, Jitendra Vohra, Charlotte Burns, Georgina Hollway, Mark Perrin, Kathryn Waddel-Smith, Michelle Cao, Ari E Horton, Matthew Perry, Mathew Wallis, Will Carr, Denise Howting, Andreas Pflaumer, Robert G Weintraub, Sarah Casauria, Jodie Ingles, Peta Phillips, Meredith Wilson, Heather Chalinor, Joanne Isbister, Thuan Phuong, David Winlaw, Yuchen Chang, Matilda Jackson, Rachel Pope-Couston, Lisa Worgan, Gavin Chapman, Paul James, Nicola K Poplawski, Linda Wornham, Theosodia Charitou, Sarah Jane-Pantaleo, Preeti Punni, Kathy Wu, Belinda Chong, Renee Johnson, Michael Cj Quinn, Laura Yeates, Felicity Collins, Andrew Kelly, Michael Quinn, Dominica Zentner, Gemma Correnti, Sarah King-Smith, Sulekha Rajagopalan, Kathy Cox, Edwin Kirk, Hariharan Raju, Fiona Cunningham, Sarah Kummerfeld, Emma M Rath, Debjani Das, Timo Lassman, Matthew Regan, Jason Davis, Jonathon Lipton, Jonathan Rogers, Andrew Davis, Sebastian Lunke, Mark Ryan, Paul De Fazio, Ivan Macciocca, Sarah Sandaradura, Michelle de Silva, Paul MacIntyre, Nicole Schonrock, Nicola Den Elzen, Evanthia O Madelli, Paul Scuffham, Sophie Devery, Amali Mallawaarachchi, Chris Semsarian, Julia Dobbins, Julia Mansour, Isabella Sherburn, Sally L Dunwoodie, Ellenore Martin, Mary-Clare Sherlock, Nathan Dwyer, Jacob Mathew, Emma Singer, Stefanie Elbracht-Leong, Tessa Mattiske, Carla Smerdon, David Elliott, Julie McGaughran, Janine Smith

Affiliations

¹ Australian Genomics, Parkville, VIC, Australia.
² Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
³ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia.
⁴ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
⁵ Murdoch Children's Research Institute, Parkville, VIC, Australia.
⁶ The Australian e-Health Research Centre, CSIRO, Herston, QLD, Australia.
⁷ Royal Children's Hospital, Parkville, VIC, Australia.
⁸ The University of Melbourne, Parkville, VIC, Australia.
⁹ Monash Children's Hospital and Monash Heart, Monash Health, Clayton, VIC, Australia.
¹⁰ Department of Genomic Medicine, The Royal Melbourne Hospital Parkville, VIC, Australia.
¹¹ Victorian Heart Institute, Monash University, Clayton, VIC, Australia.
¹² Sydney Children's Hospital Network, Westmead, NSW, Australia.
¹³ Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
¹⁴ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia.
¹⁵ SA clinical Genetics Service, Women's and Children's Hospital, North Adelaide, SA, Australia.
¹⁶ Heart Centre for Children, Sydney Children's Hospital Network, Sydney, NSW, Australia.
¹⁷ Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
¹⁸ School of Medicine, The University of Queensland, St Lucia, QLD, Australia.
¹⁹ Cardiology Department, Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
²⁰ SA Pathology, Adelaide, SA, Australia.
²¹ School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Healthcare Clinical Campus, UNSW Sydney, Darlinghurst, NSW, Australia.
²² Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia.
²³ Tasmanian Clinical Genetics Service, Tasmanian Health Service, Hobart, TAS, Australia.
²⁴ School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
²⁵ King Edward Memorial Hospital, Subiaco, WA, Australia.
²⁶ Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.
²⁷ Discipline of Paediatrics, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
²⁸ Adult Genetic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
²⁹ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.
³⁰ Cardiology Department, St Vincent's Hospital, Darlinghurst, NSW, Australia.
³¹ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

PMID: 39669597
PMCID: PMC11613726
DOI: 10.1016/j.gimo.2024.101842

Abstract

Purpose: The Australian Genomics Cardiovascular Disorders Flagship was a national multidisciplinary collaboration. It aimed to investigate the feasibility of genome sequencing (GS) and functional genomics to resolve variants of uncertain significance (VUS) in the clinical management of patients and families with cardiomyopathies, primary arrhythmias, and congenital heart disease (CHD).

Methods: Between April 2019 and December 2021, 600 probands meeting cardiovascular disorder criteria from 17 cardiology and genetics clinics across Australia were enrolled in the Flagship and underwent GS. The Flagship adopted a tiered approach to GS analysis. Tier 1 analysis assessed genes with established clinical validity for each cardiovascular condition. Tier 2 analysis assessed lesser-evidenced research-based genes. Tier 3 analysis assessed the functional impact of VUS that remained after tier 1 and tier 2 analysis.

Results: Overall, a pathogenic or likely pathogenic variant was identified in 41% of participants with a cardiomyopathy, 40% with an arrhythmia syndrome, and 15% with a familial CHD/CHD+Extra Cardiac Anomalies. A VUS outcome ranged from 13% for arrhythmias to 34% for CHD/CHD+Extra Cardiac Anomalies participants. Tier 2 research analysis identified a likely pathogenic/pathogenic variant for a further 15 participants and a VUS for an additional 15 participants.

Conclusion: The Flagship successfully facilitated a model of care that harnesses clinical GS and functional genomics for the resolution of VUS in the clinical setting. This valuable data set can be used to inform clinical practice and facilitate research into the future.

Keywords: Australian Genomics; Cardiovascular genetic disorders; Genome sequencing; Specialized multidisciplinary care.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Figure 1**
**Schema of participant recruitment, approach to clinical and research sequencing, variant curation, and the resolution of VUS.** Stages of feedback to participants are also illustrated.

**Figure 2**
**Number of participants recruited from each Australian State and Territory**.

**Figure 3**
**Summary of tier 1 clinically curated diagnostic rate (%) for the 3 clinical diagnosis categories (n = 600)**.

See this image and copyright information in PMC

References

1. Girolami F., Frisso G., Benelli M., et al. Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications. J Cardiovasc Med (Hagerstown) 2018;19(1):1–11. doi: 10.2459/JCM.0000000000000589. - DOI - PMC - PubMed
1. Isbister J., Semsarian C. Cardiovascular genomics and sudden cardiac death in the young. Aust J Gen Pract. 2019;48(3):90–95. doi: 10.31128/AJGP-09-18-4715. - DOI - PubMed
1. Pierpont M.E., Brueckner M., Chung W.K., et al. Genetic basis for congenital heart disease: revisited: a scientific statement from the American Heart Association. Circulation. 2018;138(21):e653–e711. doi: 10.1161/CIR.0000000000000606. - DOI - PMC - PubMed
1. Giudicessi J.R., Ackerman M.J., Fatkin D., Kovacic J.C. Precision medicine approaches to cardiac arrhythmias: JACC focus seminar 4/5. J Am Coll Cardiol. 2021;77(20):2573–2591. doi: 10.1016/j.jacc.2021.03.325. - DOI - PubMed
1. Fatkin D., Calkins H., Elliott P., James C.A., Peters S., Kovacic J.C. Contemporary and future approaches to precision medicine in inherited cardiomyopathies: JACC focus seminar 3/5. J Am Coll Cardiol. 2021;77(20):2551–2572. doi: 10.1016/j.jacc.2020.12.072. - DOI - PubMed

LinkOut - more resources

Full Text Sources
- Elsevier Science
- PubMed Central
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

A multitiered analysis platform for genome sequencing: Design and initial findings of the Australian Genomics Cardiovascular Disorders Flagship

Collaborators

Affiliations

A multitiered analysis platform for genome sequencing: Design and initial findings of the Australian Genomics Cardiovascular Disorders Flagship

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources

Miscellaneous