Whole genome sequencing analysis in fetal structural anomalies: novel phenotype-genotype discoveries.

OBJECTIVES: The identification of structural variants and single nucleotide variants is essential in finding molecular etiologies of monogenic genetic disorders. Whole genome sequencing (WGS) is becoming more widespread in genetic disease diagnosis. However, data on its clinical utility remain limited in prenatal practice. We aimed to expand our understanding of implementing WGS in the genetic diagnosis of fetal structural anomalies.

METHODS: We employed trio WGS with a minimum coverage of 40X on the MGI DNBSEQ-T7 platform in a cohort of 17 families with fetuses presenting with aberrations detected by ultrasonography but uninformative findings of standard chromosome microarray analysis (CMA) and exome sequencing (ES) testing.

RESULTS: Causative genetic variants were identified in two families with a diagnostic yield of 11.8% (2/17), both of which were exonic-level CNVs with small sizes of 3.03 kb and 5.16 kb beyond the detection thresholds of CMA and ES. Moreover, to the best of our knowledge, we described the first prenatal instance of FGF8 with the manifestation of holoprosencephaly and facial deformities.

CONCLUSIONS: Our analysis demonstrated the clinical value of WGS in the diagnosis of the underlying etiology of fetuses with structural abnormalities but failing to diagnose by routine genetic tests. Meanwhile, the novel variants and new fetal manifestations expanded the mutation spectrum and the phenotype spectrum of BBS9 and FGF8. This article is protected by copyright. All rights reserved.