Background Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants in RARB and STRA6, which have been previously associated with this disorder.
Methods We sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants.
Results We identified bi-allelic variants in WNT7B in fetuses with PDAC syndrome from two unrelated families. In one family, the fetus was homozygous for the c.292C>T (p.(Arg98*)) variant whereas the fetuses from the other family were compound heterozygous for the variants c.225C>G (p.(Tyr75*)) and c.562G>A (p.(Gly188Ser)). Finally, a molecular autopsy by proxy in a consanguineous couple that lost two babies due to lung hypoplasia revealed that both parents carry the p.(Arg98*) variant. Using a WNT signalling canonical luciferase assay, we demonstrated that the identified variants are deleterious. In addition, we found that wnt7bb mutant zebrafish display a defect of the swimbladder, an air-filled organ that is a structural homolog of the mammalian lung, suggesting that the function of WNT7B has been conserved during evolution for the development of these structures.
Conclusion Our findings indicate that defective WNT7B function underlies a form of lung hypoplasia that is associated with the PDAC syndrome, and provide evidence for involvement of the WNT–β-catenin pathway in human lung, tracheal, ocular, cardiac, and renal development.
- human genetics
Data availability statement
Data sharing not applicable as no datasets generated and/or analysed for this study.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
FSA, JLM and NC contributed equally.
Contributors FSA, JLM, RJ and NC contributed to the study conception and design. Patient recruitment and clinical evaluations were performed by NAA, JB, MAA, JM, SH, HSL, TAB, PC and NC. WES were performed and analysed by FH, CN, NP and FSA. Sanger sequencing were performed by SJ, PC and NC. Zebrafish studies were performed by SBou, SBoi, LFT, JMR, MM, CN, MD and SE. In vitro analyses were performed by LGR, RG, DW, IP and RJ. The first draft of the manuscript was written by SBou, JLM and NC, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. NC accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Funding This work was supported by grants from the Fondation Jeanne et Jean-Louis Lévesque (JLM), Fondation Maladies Rares (NC), Retina France (NC, LFT), NHMRC Grant 1099165 (RVJ) and Costco and Luminesce Alliance (LGR). We acknowledge Nicolas Fossat for assistance with vector cloning. We thank the Sequencing and Genotyping Core Facilities at KFSHRC for their technical help. The authors extend their appreciation to the King Salman Center For Disability Research for funding this work through Research Group no RG-2022-011. French patients were recruited through the Rares Diseases Cohorts (RaDiCo) program which is funded by the French National Research Agency under the specific program “Investments for the Future”, Cohort grant agreement ANR-10-COHO-0003.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.