Whole exome-based variant profiling and functional network characterization in neural tube defects.

backgroundNeural tube defects (NTDs) are severe congenital malformations with complex and multifactorial etiologies involving genetic, environmental, and metabolic factors. Despite folic acid fortification efforts, a considerable proportion of cases remains unexplained at the molecular level.

objectiveThis study aimed to identify rare pathogenic variants in patients with NTDs using whole exome sequencing (WES) and to evaluate their functional significance through systems biology approaches.

methodsWES was performed on nine unrelated patients with clinically diagnosed NTDs. Variants were filtered using ACMG-AMP criteria and curated via the Franklin by Genoox platform. Genes carrying pathogenic or likely pathogenic variants were analyzed using STRING for protein-protein interactions and Metascape for functional enrichment.

resultsSeven genes (PAH, ADGRG6, MPDZ, NARS1, ITGB2, PIGV, and STIL) harbored rare, clinically significant variants. Mutation types included missense, stop-gain, and frameshift, with both heterozygous and homozygous inheritance patterns. STRING analysis revealed a subnetwork involving MPDZ and ITGB2, related to tight junction integrity. Metascape analysis identified enrichment in biological processes such as catecholamine metabolism, floor plate development, and immune regulation.

conclusionThis study supports a polygenic and mechanistically diverse model of NTD pathogenesis, wherein rare variants affect developmental pathways including metabolism, cell adhesion, and neurogenesis. Integrating high-throughput sequencing with systems biology enhances variant interpretation and may inform future diagnostics and prevention strategies.