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Mouse models indicate that the homogenous disruption of the <jats:italic>Ptk7<\/jats:italic> gene, a PCP regulator, results in craniorachischisis; while embryos that are doubly heterozygous for <jats:italic>Ptk7<jats:sup>XST87<\/jats:sup><\/jats:italic> and <jats:italic>Vangl2<\/jats:italic><jats:sup>Lp <\/jats:sup>mutations present with spina bifida.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we initially sequenced exons of the human <jats:italic>PTK7<\/jats:italic> gene in 192 spina bifida patients and 190 controls from a California population. A phase II validation study was performed in 343 Chinese NTD cohort. Functional assays including immunoblotting and immunoprecipitation were used to study identified variants effect on PTK7 function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified three rare (MAF &lt;0.001) missense heterozygous <jats:italic>PTK7<\/jats:italic> variants (NM_001270398.1:c.581C&gt;T, p.Arg630Ser and p.Tyr725Phe) in the spina bifida patients. In our functional analyses, p.Arg630Ser affected PTK7 mutant protein stability and increased interaction with Dvl2, while the p.Thr186Met variant decreased PTK7 interactions with Dvl2. No novel predicted\u2010to\u2010be\u2010damaging variant or function\u2010disrupted <jats:italic>PTK7<\/jats:italic> variant was identified among the control subjects. We subsequently re\u2010sequenced the <jats:italic>PTK7<\/jats:italic> CDS region in 343 NTDs from China to validate the association between <jats:italic>PTK7<\/jats:italic> and NTDs. The frequency of <jats:italic>PTK7<\/jats:italic> rare missense variants in the Chinese NTD samples is significantly higher than in gnomAD controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study suggests that rare missense variants in <jats:italic>PTK7<\/jats:italic> contribute to the genetic risk of NTDs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.584","type":"journal-article","created":{"date-parts":[[2019,1,28]],"date-time":"2019-01-28T22:01:11Z","timestamp":1548712871000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Variants identified in <i>PTK7<\/i> associated with neural tube defects"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1504-0884","authenticated-orcid":false,"given":"Yunping","family":"Lei","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School Austin Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung\u2010Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School Austin Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongzhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanye","family":"Cao","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Biology and Medicine Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiping","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School Austin Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatology Stanford University School of Medicine Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary M.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatology Stanford University School of Medicine Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Municipal Key Laboratory of Child Development and Nutriomics Capital Institute of Pediatrics Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5962-8754","authenticated-orcid":false,"given":"Richard H.","family":"Finnell","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School Austin Texas"},{"name":"Collaborative Innovation Center for Genetics &amp; 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