The Australian PreGen Study: Results From Prospective Prenatal Exome Sequencing in 275 Pregnancies

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.

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.

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.

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.