The planar cell polarity (PCP) pathway is critical for proper embryonic development of the neural tube and heart. Mutations in these genes have previously been implicated in the pathogenesis of neural tube defects (NTDs), but not in congenital heart defects (CHDs) in humans. We systematically identified the mutation patterns of CELSR1–3, one family of the core PCP genes, in human cohorts composed of 352 individuals with NTDs, 412 with CHDs and matched controls. A total of 72 disease-specific, rare, novel, coding mutations were identified, of which 37 were identified in patients with CHDs and 36 in patients with NTDs. Most of these mutations differed between the two cohorts, because only one novel missense mutation in CELSR1 (c.2609G>A p.P870L) was identified in both NTD and CHD patients. Both in vivo and in vitro assays revealed that CELSR1 P870L is a gain-of-function mutation. It up-regulates not only the PCP pathway, but also canonical WNT signalling in cells, and also induces both NTDs and CHDs in zebrafish embryos. As almost equal numbers of mutations were identified in each cohort, our results provided the first evidence that mutations in CELSR genes are as likely to be associated with CHDs as with NTDs, although the specific mutations differ between the two cohorts. Such differences in mutation panels suggested that CELSRs [cadherin, EGF (epidermal growth factor), LAG (laminin A G-type repeat), seven-pass receptors)] might be regulated differently during the development of these two organ systems.

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