Whole-genome sequencing for the prenatal evaluation of fetal structural anomalies: a prospective multicenter study.

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

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

Study design: Whole-genome sequencing was performed in parallel with copy-number variant sequencing and exome sequencing 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 the American College of Medical Genetics and Genomics, Association for Molecular Pathology, and ClinGen guidelines.

Results: Diagnostic variants were found by copy-number variant sequencing for 5/96 (5.2%) fetuses and by trio-exome sequencing for 26/96 (27.1%) fetuses. The combined diagnostic rate for copy-number variant sequencing plus trio-exome sequencing was 30/96 (31.2%). Whole-genome sequencing identified all diagnostic variants detected by copy-number variant sequencing and trio-exome sequencing plus 3 additional fetuses (one with maternal uniparental disomy 15, one with a complex chromosomal rearrangement, and one with compound heterozygous single-nucleotide variants 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 7 fetuses were detected only by whole-genome sequencing, including 6 inversions and one uniparental disomy 16.

Conclusion: Trio-based whole-genome sequencing offers a valid alternative to copy-number variant sequencing plus exome sequencing, demonstrating the capacity for more comprehensive genomic analysis for fetuses with structural anomalies while permitting consolidation of laboratory workflows into a single test.