Whole exome-based variant profiling and functional network characterization in neural tube defects
Nermin Akcali1,2, Saliha Handan Yildiz3, Mujgan Ozdemir Erdogan3
1Faculty of Engineering and Natural Sciences, Department of Molecular Biology and Genetics, Biruni University, Istanbul, 34015, Turkey. nakcali@biruni.edu.tr.
Summary
Rare genetic variants contribute to neural tube defects (NTDs) beyond folic acid, impacting development. Systems biology aids understanding of these complex conditions for better diagnostics and prevention.
Area of Science:
- Genetics
- Developmental Biology
- Systems Biology
Background:
- Neural tube defects (NTDs) are severe congenital malformations with complex, multifactorial causes.
- Genetic, environmental, and metabolic factors contribute to NTDs.
- Folic acid fortification has not fully explained all NTD cases at the molecular level.
Purpose of the Study:
- To identify rare pathogenic variants in patients with NTDs using whole exome sequencing (WES).
- To evaluate the functional significance of identified variants through systems biology approaches.
Main Methods:
- Whole exome sequencing (WES) on nine unrelated patients with NTDs.
- Variant filtering using ACMG-AMP criteria and the Franklin by Genoox platform.
- Protein-protein interaction and functional enrichment analyses using STRING and Metascape.
Main Results:
- Seven genes (PAH, ADGRG6, MPDZ, NARS1, ITGB2, PIGV, STIL) harbored rare, clinically significant variants.
- Identified missense, stop-gain, and frameshift mutations with heterozygous and homozygous patterns.
- Discovered a subnetwork (MPDZ, ITGB2) linked to tight junctions and enriched pathways in catecholamine metabolism, floor plate development, and immune regulation.
Conclusions:
- Supports a polygenic and mechanistically diverse model for NTD pathogenesis.
- Rare variants impact key developmental pathways: metabolism, cell adhesion, and neurogenesis.
- Integrating WES with systems biology improves variant interpretation for diagnostics and prevention.
