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
Affiliations
- Rachel Austin
- Australian Genomics, Parkville, VIC, Australia; Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
- Jaye S. Brown
- Australian Genomics, Parkville, VIC, Australia; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia; Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Sarah Casauria
- Australian Genomics, Parkville, VIC, Australia; Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Evanthia O. Madelli
- Australian Genomics, Parkville, VIC, Australia; Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Tessa Mattiske
- Australian Genomics, Parkville, VIC, Australia
- Tiffany Boughtwood
- Australian Genomics, Parkville, VIC, Australia; Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Alejandro Metke
- The Australian e-Health Research Centre, CSIRO, Herston, QLD, Australia
- Andrew Davis
- Murdoch Children’s Research Institute, Parkville, VIC, Australia; Royal Children’s Hospital, Parkville, VIC, Australia; The University of Melbourne, Parkville, VIC, Australia
- Ari E. Horton
- Monash Children’s Hospital and Monash Heart, Monash Health, Clayton, VIC, Australia; Department of Genomic Medicine, The Royal Melbourne Hospital Parkville, VIC, Australia; Victorian Heart Institute, Monash University, Clayton, VIC, Australia
- David Winlaw
- Sydney Children’s Hospital Network, Westmead, NSW, Australia
- Debjani Das
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
- Magdalena Soka
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
- Eleni Giannoulatou
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia
- Emma M. Rath
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia
- Eric Haan
- SA clinical Genetics Service, Women’s and Children’s Hospital, North Adelaide, SA, Australia
- Gillian M. Blue
- Heart Centre for Children, Sydney Children’s Hospital Network, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Jitendra Vohra
- The University of Melbourne, Parkville, VIC, Australia; Department of Genomic Medicine, The Royal Melbourne Hospital Parkville, VIC, Australia
- John J. Atherton
- School of Medicine, The University of Queensland, St Lucia, QLD, Australia; Cardiology Department, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
- Karin van Spaendonck-Zwarts
- Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
- Kathy Cox
- SA Pathology, Adelaide, SA, Australia
- Leslie Burnett
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; School of Clinical Medicine, UNSW Medicine and Health, St Vincent’s Healthcare Clinical Campus, UNSW Sydney, Darlinghurst, NSW, Australia; Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
- Mathew Wallis
- Tasmanian Clinical Genetics Service, Tasmanian Health Service, Hobart, TAS, Australia; School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
- Matilda Haas
- Australian Genomics, Parkville, VIC, Australia; Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Michael C.J. Quinn
- Australian Genomics, Parkville, VIC, Australia; Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
- Nicholas Pachter
- King Edward Memorial Hospital, Subiaco, WA, Australia; Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia
- Nicola K. Poplawski
- Discipline of Paediatrics, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia; Adult Genetic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
- Zornitza Stark
- Australian Genomics, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Richard D. Bagnall
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia
- Robert G. Weintraub
- Murdoch Children’s Research Institute, Parkville, VIC, Australia; Royal Children’s Hospital, Parkville, VIC, Australia; The University of Melbourne, Parkville, VIC, Australia
- Sarah-Jane Pantaleo
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Sebastian Lunke
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Paul De Fazio
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Tina Thompson
- The University of Melbourne, Parkville, VIC, Australia; Department of Genomic Medicine, The Royal Melbourne Hospital Parkville, VIC, Australia
- Paul James
- Department of Genomic Medicine, The Royal Melbourne Hospital Parkville, VIC, Australia
- Yuchen Chang
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia
- Diane Fatkin
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia; Cardiology Department, St Vincent’s Hospital, Darlinghurst, NSW, Australia
- Ivan Macciocca
- Royal Children’s Hospital, Parkville, VIC, Australia; The University of Melbourne, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Jodie Ingles
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
- Sally L. Dunwoodie
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia
- Chris Semsarian
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia; Christopher Semsarian, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown NSW 2042 Australia.
- Julie McGaughran
- Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia; School of Medicine, The University of Queensland, St Lucia, QLD, Australia; Correspondence and requests for materials should be addressed to Julie McGaughran, Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD, 4029, Australia.
- 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
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Vol. 2
p. 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.
