Targeted Re-Sequencing of Neural Tube Defects Patients and Families Identifies Rare Variants in Genes Candidate From Animal Models.

Background/objectives: Neural tube defects (NTDs) are congenital malformations arising when the neural tube (NT), precursor of the brain and spine, fails to properly close during neurulation. Etiology is multifactorial, with environmental and genetic factors variably contributing on a case-by-case basis. Molecular genetic studies of murine NTD genes have been precious in the identification of predisposing NTD genes in humans, highlighting the peculiar role of the planar cell polarity (PCP) pathway in a fraction of human NTD patients.

Methods: Seventy-eight patients with NTD treated at a pediatric tertiary care center were selected for genetic analysis. A custom next-generation sequencing (NGS) panel of 29 genes encoding for components of the core PCP pathway or for family members and paralogs of proteins (including SHROOM and GRHL) underlying NTDs in well-known animal models was used to re-sequence patients with NTD. A gene-burden analysis was also performed to assess potential enrichment of rare damaging variants in the NTD cohort compared to ethnically matched controls.

Results: Thirty-nine of 78 individuals (50%) presented with at least one putatively damaging rare variant, most of which (87%) were missense substitutions. Rare variants of GRHL1 and WNT5A, and among gene families GRHL and SHROOM, were significantly enriched in the patients' cohort compared to controls.

Conclusion: This study supports the involvement of human orthologues of mouse genes in human NTD phenotypes. Further re-sequencing or, even better, whole-exome sequencing of a large group of cases will give the clues for a better understanding of NTD etiology, ameliorating the clinical management of patients and their families.