Optical genome mapping identifies rare structural variants in neural tube defects

Neural tube defects (NTDs) are the most common birth defects of the central nervous system and occur as either isolated malformations or accompanied by anomalies of other systems. The genetic basis of NTDs remains poorly understood using karyotyping, chromosomal microarray, and short-read sequencing, with only a limited number of pathogenic variants identified. Collectively, these technologies may fail to detect rare structural variants (SVs) in the genome, which may cause these birth defects. Therefore, optical genome mapping (OGM) was applied to investigate 104 NTD cases, of which 74 were isolated NTDs and 30 were NTDs with other malformations. A stepwise approach was undertaken to ascertain candidate variants using population and internal databases and performing parental studies when possible. This analysis identifies diagnostic findings in 8% of cases (8/104) and candidate findings in an additional 22% of cases (23/104). Of the candidate findings, 9% of cases (9/104) have SVs impacting genes associated with NTDs in mouse, and 13% of cases (14/104) have SVs impacting genes implicated in the neural tube development pathways. This study identifies RMND5A, HNRNPC, FOXD4, and RBBP4 as strong candidate genes associated with NTDs, and expands the phenotypic spectrum of AMER1 and TGIF1 to include NTDs. This study constitutes the first systematic investigation of SVs using OGM to elucidate the genetic determinants of NTDs. The data provide key insights into the pathogenesis of NTDs and demonstrate the contribution of SVs in the genome to these birth defects.