Conor Rowntree, Gemma Fernihough, Sarah Long, Mohammad Al-Shinnag, Alyssa Wilson, Jayamala Parmar, Natalie Hart, Mandi MacShane, Kate Ross, Di Milnes, Benjamin Kamien, Jan E Dickinson, Jon Hyett, John Smoleniec, Lesley McGregor, Rachael Stenhouse, Rebecca Vink, Sebastian Lunke, Meg Wall, Lucas de Jong, Abhijit Kulkarni, Rosalie Kenyon, Jinghua Feng, Matilda R Jackson, Karin Kassahn, Hamish S Scott, Edwin Kirk, Martin Smith, Futao Zhang, Josh Kraindler, Luke Rynehart, Rupendra Shrestha, Deborah Schofield, Ying Zhu, Michael F Buckley, George McGillivray, Tony Roscioli, PreGen Consortium
pES demonstrated a high diagnostic yield with low VOUS and incidental finding rates. Outcomes differed between diagnosed and uninformative families, with TOP more frequent after genomic diagnoses. These findings support pES as a core diagnostic test for antenatal FSA evaluation and emphasise the importance of consistent phenotype ontology, body system classification, and eligibility criteria for fetal genomic sequencing.
OBJECTIVE: Prenatal exome sequencing (pES) is increasingly to standard care for diagnosing the etiology of fetal structural anomalies (FSA). We evaluated trio pES outcomes in the national multicentre, prospectively recruited Australian Government-funded cohort, including diagnostic yield, frequency of variants of uncertain significance (VOUS), incidental findings and impacts on pregnancy management.
METHOD: Prospective referral and analysis were undertaken for 275 consented families nation-wide for trio pES. Eligibility was based on predefined FSA criteria and an uninformative chromosome microarray. Sequencing was performed in one of three clinically accredited national referral laboratories.
RESULTS: The pES diagnostic yield for pathogenic/likely pathogenic variants was 31.6% (87/275, 95% CI; 26.4-37.4). VOUS and incidental findings occurred at a rate of 4.4% (12/275) and 1.5% (4/275) respectively. Termination of pregnancy (TOP) occurred more frequently in diagnosed families, whereas live births were more common in the uninformative cohort.
CONCLUSION: pES demonstrated a high diagnostic yield with low VOUS and incidental finding rates. Outcomes differed between diagnosed and uninformative families, with TOP more frequent after genomic diagnoses. These findings support pES as a core diagnostic test for antenatal FSA evaluation and emphasise the importance of consistent phenotype ontology, body system classification, and eligibility criteria for fetal genomic sequencing.