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Mol Genet Genomic Med. 2019 Apr;7(4):e00584. doi: 10.1002/mgg3.584. Epub 2019 Jan 28.

Variants identified in PTK7 associated with neural tube defects.

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Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School, Austin, Texas.
Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai, China.
Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, Texas.
Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, California.
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
Collaborative Innovation Center for Genetics & Development, School of Life Sciences, Fudan University, Shanghai, China.



Variants in planar cell polarity (PCP) pathway genes have been repeatedly implicated in the pathogenesis of NTDs in both mouse models and in human cohorts. Mouse models indicate that the homogenous disruption of the Ptk7 gene, a PCP regulator, results in craniorachischisis; while embryos that are doubly heterozygous for Ptk7XST87 and Vangl2Lp mutations present with spina bifida.


In this study, we initially sequenced exons of the human PTK7 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.


We identified three rare (MAF <0.001) missense heterozygous PTK7 variants (NM_001270398.1:c.581C>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-to-be-damaging variant or function-disrupted PTK7 variant was identified among the control subjects. We subsequently re-sequenced the PTK7 CDS region in 343 NTDs from China to validate the association between PTK7 and NTDs. The frequency of PTK7 rare missense variants in the Chinese NTD samples is significantly higher than in gnomAD controls.


Our study suggests that rare missense variants in PTK7 contribute to the genetic risk of NTDs.


PTK7 ; neural tube defects; planar cell polarity

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