Genetics in Medicine Open (Jan 2024)

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

  • Rachel Austin,
  • Jaye S. Brown,
  • Sarah Casauria,
  • Evanthia O. Madelli,
  • Tessa Mattiske,
  • Tiffany Boughtwood,
  • Alejandro Metke,
  • Andrew Davis,
  • Ari E. Horton,
  • David Winlaw,
  • Debjani Das,
  • Magdalena Soka,
  • Eleni Giannoulatou,
  • Emma M. Rath,
  • Eric Haan,
  • Gillian M. Blue,
  • Jitendra Vohra,
  • John J. Atherton,
  • Karin van Spaendonck-Zwarts,
  • Kathy Cox,
  • Leslie Burnett,
  • Mathew Wallis,
  • Matilda Haas,
  • Michael C.J. Quinn,
  • Nicholas Pachter,
  • Nicola K. Poplawski,
  • Zornitza Stark,
  • Richard D. Bagnall,
  • Robert G. Weintraub,
  • Sarah-Jane Pantaleo,
  • Sebastian Lunke,
  • Paul De Fazio,
  • Tina Thompson,
  • Paul James,
  • Yuchen Chang,
  • Diane Fatkin,
  • Ivan Macciocca,
  • Jodie Ingles,
  • Sally L. Dunwoodie,
  • Chris Semsarian,
  • Julie McGaughran,
  • 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 C.J. 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

Journal volume & issue
Vol. 2
p. 101842

Abstract

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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.

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