Detection of genomic variants by genome sequencing in foetuses with central nervous system abnormalities.

Objective: Clinical validity of genome sequencing (GS) (>30×) has been preliminarily verified in the post-natal setting. This study is to investigate the potential utility of trio-GS as a prenatal test for diagnosis of central nervous system (CNS) anomalies.

Methods: We performed trio-based GS on a prospective cohort of 17 foetuses with CNS abnormalities. Single nucleotide variation (SNV), small insertion and deletion (Indel), copy number variation (CNV), structural variant (SV), and regions with absence of heterozygosity (AOH) were analyzed and classified according to ACMG guidelines.

Results: Trio-GS identified diagnostic findings in 29.4% (5/17) of foetuses, with pathogenic variants found in , , and . Corpus callosum (CC) and cavum septum pellucidum (CSP) abnormalities were the most frequent CNS abnormalities (47.1%, 8/17) with a diagnostic yield of 50%. A total of 29.4% (5/17) foetuses had variants of uncertain significance (VUS). Particularly, maternal uniparental disomy 16 and a mosaic 4p12p11 duplication were simultaneously detected in one foetus with abnormal sulcus development. In addition, parentally inherited chromosomal inversions were identified in two foetuses.

Conclusion: GS demonstrates its feasibility in providing genetic diagnosis for foetal CNS abnormalities and shows the potential to expand the application to foetuses with other ultrasound anomalies in prenatal diagnosis.