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Original research
DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes
  1. Jonathan Marquez1,
  2. Nina Mann2,
  3. Kathya Arana3,
  4. Engin Deniz3,
  5. Weizhen Ji3,
  6. Monica Konstantino3,
  7. Emily K Mis3,
  8. Charu Deshpande4,
  9. Lauren Jeffries3,
  10. Julie McGlynn5,
  11. Hannah Hugo2,
  12. Eugen Widmeier2,
  13. Martin Konrad6,
  14. Velibor Tasic7,
  15. Raffaella Morotti8,
  16. Julia Baptista9,10,
  17. Sian Ellard9,10,
  18. Saquib Ali Lakhani3,
  19. Friedhelm Hildebrandt2,
  20. Mustafa K Khokha1
  1. 1Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
  2. 2Division of Nephrology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  3. 3Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
  4. 4Department of Clinical Genetics, Guy's Hospital, London, UK
  5. 5Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA
  6. 6Department of General Pediatrics, University Hospital Münster, Münster, Germany
  7. 7Department of Pediatric Nephrology, University Children's Hospital, Skopje, North Macedonia
  8. 8Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
  9. 9Exeter Genomics Laboratory, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK
  10. 10Institute of Biomedical & Clinical Science, College of Medicine and Health, Exeter, UK
  1. Correspondence to Dr Mustafa K Khokha, Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; mustafa.khokha{at}


Background Cilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.

Methods Among individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model.

Results Patients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.

Conclusion These findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.

  • genetics
  • hydrocephalus
  • molecular genetics
  • renal medicine
  • developmental

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  • Contributors NM, WJ, MK, EKM, CD, LJ, JMcG, VT, SAL, FH and MKK recruited patients and gathered detailed clinical information for the study. WJ, HH, EW, JB, SE, SAL, FH, MKK performed whole exome evaluation and variant analysis. JM, KA and ED performed Xenopus experiments. RM obtained pathological sections of tissue. JM performed imaging and analysis of patient tissue. All authors critically reviewed the paper. JM, SAL and MKK conceived of and directed the project. JM, LJ, SAL and MKK wrote the paper.

  • Funding JM is supported by the Yale MSTP NIH T32GM007205 Training Grant, the Yale Predoctoral Program in Cellular and Molecular Biology T32GM007223 Training Grant and the Paul and Daisy Soros Fellowship for New Americans. EKM is supported by a grant from the Hartwell Foundation and is a Hartwell Fellow. EW is supported by the Leopoldina Fellowship Program (LPDS 2015-07). MK is part of the NEOCYST consortium funded by the German Federal Ministry of Research and Education (BMBF, grant 01GM1903A). SE is a Wellcome Senior Investigator. This research was supported by grants from the National Institutes of Health to FH (DK076683, DK088767, DK068306). NM is supported by funding from the National Institutes of Health T32-DK007726-33 grant at Boston Children's Hospital. MKK is supported by NIH/NICHD (R01HD102186).

  • Competing interests FH is a cofounder of Goldfinch Biopharma. SAL is part owner of Qiyas Higher Health.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Institutional Review Board at Yale University. Acquisition of patient tissue was conducted in accordance with the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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