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

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

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.

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.

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.

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.