{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T19:57:54Z","timestamp":1757620674291,"version":"3.44.0"},"reference-count":33,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background\/Objectives<\/jats:title><jats:p>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\u2010by\u2010case 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Seventy\u2010eight patients with NTD treated at a pediatric tertiary care center were selected for genetic analysis. A custom next\u2010generation 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\u2010known animal models was used to re\u2010sequence patients with NTD. A gene\u2010burden analysis was also performed to assess potential enrichment of rare damaging variants in the NTD cohort compared to ethnically matched controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty\u2010nine of 78 individuals (50%) presented with at least one putatively damaging rare variant, most of which (87%) were missense substitutions. Rare variants of <jats:italic>GRHL1<\/jats:italic> and <jats:italic>WNT5A<\/jats:italic>, and among gene families <jats:italic>GRHL<\/jats:italic> and <jats:italic>SHROOM<\/jats:italic>, were significantly enriched in the patients' cohort compared to controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study supports the involvement of human orthologues of mouse genes in human NTD phenotypes. Further re\u2010sequencing or, even better, whole\u2010exome 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.2507","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T11:49:24Z","timestamp":1752752964000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Re\u2010Sequencing of Neural Tube Defects Patients and Families Identifies Rare Variants in Genes Candidate From Animal Models"],"prefix":"10.1002","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3933-0597","authenticated-orcid":false,"given":"Ferruccio","family":"Romano","sequence":"first","affiliation":[{"name":"Genomics and Clinical Genetics Unit IRCCS Istituto Giannina Gaslini  Genoa 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