Austin Rachel, Brown Jaye S, Casauria Sarah, Madelli Evanthia O, Mattiske Tessa, Boughtwood Tiffany, Metke Alejandro, Davis Andrew, Horton Ari E, Winlaw David, Das Debjani, Soka Magdalena, Giannoulatou Eleni, Rath Emma M, Haan Eric, Blue Gillian M, Vohra Jitendra, Atherton John J, van Spaendonck-Zwarts Karin, Cox Kathy, Burnett Leslie, Wallis Mathew, Haas Matilda, Quinn Michael C J, Pachter Nicholas, Poplawski Nicola K, Stark Zornitza, Bagnall Richard D, Weintraub Robert G, Pantaleo Sarah-Jane, Lunke Sebastian, De Fazio Paul, Thompson Tina, James Paul, Chang Yuchen, Fatkin Diane, Macciocca Ivan, Ingles Jodie, Dunwoodie Sally L, Semsarian Chris, McGaughran Julie
Australian Genomics, Parkville, VIC, Australia.
Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
Genet Med Open. 2024 Mar 25;2:101842. doi: 10.1016/j.gimo.2024.101842. eCollection 2024.
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).
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.
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.
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.
澳大利亚基因组学心血管疾病旗舰项目是一项全国性的多学科合作。其旨在研究基因组测序（GS）和功能基因组学在心肌病、原发性心律失常和先天性心脏病（CHD）患者及家庭临床管理中解决意义未明变异（VUS）的可行性。
在2019年4月至2021年12月期间，来自澳大利亚17家心脏病学和遗传学诊所的600名符合心血管疾病标准的先证者被纳入该旗舰项目并接受了GS检测。该旗舰项目采用分层方法进行GS分析。一级分析评估每种心血管疾病已确立临床有效性的基因。二级分析评估证据较少的基于研究的基因。三级分析评估一级和二级分析后仍存在的VUS的功能影响。
总体而言，在41%的心肌病参与者、40%的心律失常综合征参与者和15%的家族性CHD/CHD+心脏外异常参与者中鉴定出致病性或可能致病性变异。VUS结果在心律失常参与者中为13%，在CHD/CHD+心脏外异常参与者中为34%。二级研究分析又为另外15名参与者鉴定出可能致病性/致病性变异，为另外15名参与者鉴定出VUS。
该旗舰项目成功推动了一种医疗模式，即在临床环境中利用临床GS和功能基因组学来解决VUS。这个有价值的数据集可用于为临床实践提供信息并促进未来的研究。
