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

Trio prenatal exome sequencing after an uninformative chromosomal microarray, with analysis of diagnostic yield, variants of uncertain significance, incidental findings and the impact on pregnancy management

Prenatal exome sequencing (pES) is increasingly integrated into standard care to establish the aetiology of fetal structural anomalies (FSA). The authors evaluate trio pES outcomes in the national multicentre, prospectively recruited, Australian Government-funded cohort, analysing diagnostic yield, the frequency of variants of uncertain significance (VUS), incidental findings and the impact on pregnancy management: 275 consenting families were included on predefined FSA criteria and an uninformative chromosomal microarray, with sequencing performed in one of three clinically accredited national referral laboratories. The diagnostic yield for pathogenic or likely pathogenic variants is 31.6% (87/275; 95% CI 26.4 to 37.4%), with VUS and incidental findings occurring in 4.4% (12/275) and 1.5% (4/275) of cases respectively. Termination of pregnancy is more frequent in diagnosed families, whereas live births predominate in the uninformative cohort, and the authors conclude that pES is a core diagnostic test for antenatal FSA evaluation, stressing the importance of a consistent phenotype ontology, body-system classification and eligibility criteria.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A yield of 31.6% with only 4.4% of variants of uncertain significance and 1.5% of incidental findings is a favourable profile, and obtaining it in a prospective national trio cohort gives it a weight that retrospective series lack. The most sensitive point for counselling is the difference in outcomes: termination of pregnancy is more frequent after a genomic diagnosis, which requires this result to be prepared for at the pretest consultation, without being able to separate the effect of the diagnosis from that of the severity of the underlying anomaly. This yield applies to families selected by predefined criteria and an uninformative microarray, and the authors themselves stress that harmonised eligibility criteria and phenotype classification condition comparability between studies.

Analysis by Dr Thibaut Benquey