Whole-Genome Sequencing for the Prenatal Evaluation of Fetal Structural Anomalies: A prospective multicenter study.

Background: The clinical validity of whole-genome sequencing (WGS) in postnatal settings is well documented, but studies of its use in prenatal settings are limited.

Objectives: The objective of this study was to prospectively evaluate the performance of whole-genome sequencing (WGS) for prenatal diagnosis of fetal structural anomalies compared with the commonly used testing strategy of copy-number variant sequencing (CNV-seq) plus exome sequencing (ES).

Study Design: WGS was performed in parallel with CNV-seq and ES for 96 parent-fetus trios with fetal structural anomalies. Single-nucleotide variants, small insertions/deletions, copy-number variations, structural variants, and absence of heterozygosity were classified according to American College of Medical Genetics and Genomics, Association for Molecular Pathology, and ClinGen guidelines.

Results: Diagnostic variants were found by CNV-seq for 5/96 (5.2%) fetuses and by trio-ES for 26/96 (27.1%) fetuses. The combined diagnostic rate for CNV-seq plus trio-ES was 30/96 (31.2%). Trio-WGS identified all diagnostic variants detected by CNV-seq and trio-ES plus three additional fetuses (one with maternal UPD15, one with a complex chromosomal rearrangement and one with compound heterozygous SNVs in NADSYN1), increasing the diagnostic rate to 33/96 (34.4%). The highest diagnostic rate was observed in fetuses with craniofacial abnormalities (2/3, 66.7%), followed by those with hydrops (3/6, 50.0%). Ten families (10.5%, 10/96) were detected with incidental findings, of which, structural variants in seven fetuses were detected only by trio-WGS, including six inversions and one UPD16.

Conclusions: Trio-based WGS offers a valid alternative to CNV-seq plus ES, demonstrating the capacity for more comprehensive genomic analysis for fetuses with structural anomalies while permitting consolidation of laboratory workflows into a single test.