학술논문
A multitiered analysis platform for genome sequencing: Design and initial findings of the Australian Genomics Cardiovascular Disorders Flagship
Document Type
article
Author
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; James McNamara; Morgan almog; Vanessa Fear; Caroline Medi; Mohammad Al-Shinnag; Miriam Fine; Raymond Sy; Keri Finlay; Di Milnes; Dotti Tang; Denisse Garza; Michael Milward; Jessica Taylor; Ansley Morrish; Shelby Taylor; Chris Barnett; Laura Gongolidis; Jim Morwood; Michel Tchan; Belinda Gray; Helen Mountain; Simon Bodek; Cassie Greer; David Mowat; Jordan Thorpe; Kirsten Boggs; Chai-Ann Ng; Alison Trainer; Michael Bogwitz; Mathilda Haas; Natalie Nowak; Gunjan Trivedi; Bernadette Hanna; Noelia Nunez Martinez; Giulia Valente; Alessandra Bray; Richard Harvey; Monique Ohanian; Marie-Jo Brion; Janette Hayward; Sinead O’Sullivan; Jamie Vandenberg; Jaye Brown; Carmen Herrera; Angela Overkov; Kunal Verma; Rob Bryson Richardson; Adam Hill; Miranda Vidgen; Georgie Hollingsworth; Chirag Patel; Charlotte Burns; Georgina Hollway; Mark Perrin; Kathryn Waddel-Smith; Michelle Cao; Matthew Perry; Will Carr; Denise Howting; Andreas Pflaumer; Peta Phillips; Meredith Wilson; Heather Chalinor; Joanne Isbister; Thuan Phuong; Matilda Jackson; Rachel Pope-Couston; Lisa Worgan; Gavin Chapman; Linda Wornham; Theosodia Charitou; Sarah Jane-Pantaleo; Preeti Punni; Kathy Wu; Belinda Chong; Renee Johnson; Laura Yeates; Felicity Collins; Andrew Kelly; Michael Quinn; Dominica Zentner; Gemma Correnti; Sarah King-Smith; Sulekha Rajagopalan; Edwin Kirk; Hariharan Raju; Fiona Cunningham; Sarah Kummerfeld; Timo Lassman; Matthew Regan; Jason Davis; Jonathon Lipton; Jonathan Rogers; Mark Ryan; Sarah Sandaradura; Michelle de Silva; Paul MacIntyre; Nicole Schonrock; Nicola Den Elzen; Paul Scuffham; Sophie Devery; Amali Mallawaarachchi; Julia Dobbins; Julia Mansour; Isabella Sherburn; Ellenore Martin; Mary-Clare Sherlock; Nathan Dwyer; Jacob Mathew; Emma Singer; Stefanie Elbracht-Leong; Carla Smerdon; David Elliott; Janine Smith
Source
Genetics in Medicine Open, Vol 2, Iss , Pp 101842- (2024)
Subject
Language
English
ISSN
2949-7744
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.