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Original research
Bi-allelic variants in WNT7B disrupt the development of multiple organs in humans
  1. Samir Bouasker1,
  2. Nisha Patel2,
  3. Rebecca Greenlees3,
  4. Diana Wellesley4,
  5. Lucas Fares Taie5,
  6. Naif A Almontashiri6,7,
  7. Julia Baptista8,9,
  8. Malak Ali Alghamdi10,
  9. Sarah Boissel1,
  10. Jelena Martinovic11,
  11. Ivan Prokudin3,
  12. Samantha Holden12,
  13. Hardeep-Singh Mudhar13,
  14. Lisa G Riley14,15,
  15. Christina Nassif1,
  16. Tania Attie-Bitach16,
  17. Marguerite Miguet1,
  18. Marion Delous17,
  19. Sylvain Ernest16,
  20. Julie Plaisancié18,19,20,
  21. Patrick Calvas18,19,
  22. Jean-Michel Rozet5,
  23. Arif O Khan21,
  24. Fadi F Hamdan1,
  25. Robyn V Jamieson3,22,
  26. Fowzan S Alkuraya2,23,
  27. Jacques L Michaud24,25,
  28. Nicolas Chassaing18,19
  1. 1 Research Center, University Hospital Centre Sainte-Justine, Montreal H3T 1C5, Québec, Canada
  2. 2 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  3. 3 Eye Genetics Research Unit, Children's Medical Research Institute, University of Sydney; The Children’s Hospital at Westmead, Sydney Children’s Hospitals Network; and Save Sight Institute, Sydney, New South Wales, Australia
  4. 4 Wessex Clinical Genetic Service, University Hospital Southampton, Southampton, UK
  5. 5 Laboratory Genetics in Ophthalmology, INSERM UMR1163, Imagine Institute for Genetic Diseases, Université Paris Descartes-Sorbonne, Paris, Île-de-France, France
  6. 6 Center for Genetics and Inherited Diseases (CGID), Taibah University, Madinah, Al Madinah, Saudi Arabia
  7. 7 Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  8. 8 Peninsula Medical School, Faculty of Health, University of Plymouth, Plymouth, UK
  9. 9 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
  10. 10 Medical Genetic Division, Pediatric Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  11. 11 Unit of Fetal Pathology, APHP Hopital Antoine-Beclere, Clamart, Île-de-France, France
  12. 12 Department of Cellular Pathology, University Hospital Southampton, Southampton, UK
  13. 13 National Specialist Ophthalmic Pathology Service (NSOPS), Dept of Histopathology, Royal Hallamshire Hospital, Sheffield, UK
  14. 14 Rare Diseases Functional Genomics Laboratory, The Children’s Hospital at Westmead, Sydney Children’s Hospitals Network, Children's Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia
  15. 15 Specialty of Paediatrics and Child Health, Faculty of Medicine and Health, University of Sydney, Sidney, New South Wales, Australia
  16. 16 Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Imagine Institute for Genetic Diseases, Paris, Île-de-France, France
  17. 17 Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, Auvergne-Rhône-Alpes, France
  18. 18 Department of Medical Genetics, Purpan University Hospital, Toulouse, Midi-Pyrénées, France
  19. 19 Centre de Référence des Affections Rares en Génétique Ophtalmologique CARGO, Site Constitutif, Purpan University Hospital, Toulouse, Midi-Pyrénées, France
  20. 20 INSERM U1214, ToNIC, Université Toulouse III, Toulouse, France
  21. 21 Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, Abu Dhabi, UAE
  22. 22 Specialty of Genomic Medicine, Faculty of Medicine and Health and Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia
  23. 23 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
  24. 24 Departments of Pediatrics and Neurosciences, Université de Montréal, Montreal H3T 1J4, Québec, Canada
  25. 25 Departments of Pediatrics and Neurosciences, Université de Montréal, Montreal, Québec, Canada
  1. Correspondence to Dr Nicolas Chassaing, Department of Medical Genetics, Hospital Purpan, Toulouse, Midi-Pyrénées, France; chassaing.n{at}; Dr Jacques L Michaud;{at}; Dr Fowzan S Alkuraya; FAlKuraya{at}


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.

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Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

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  • 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.