RT Journal Article SR Electronic T1 DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2019-106805 DO 10.1136/jmedgenet-2019-106805 A1 Jonathan Marquez A1 Nina Mann A1 Kathya Arana A1 Engin Deniz A1 Weizhen Ji A1 Monica Konstantino A1 Emily K Mis A1 Charu Deshpande A1 Lauren Jeffries A1 Julie McGlynn A1 Hannah Hugo A1 Eugen Widmeier A1 Martin Konrad A1 Velibor Tasic A1 Raffaella Morotti A1 Julia Baptista A1 Sian Ellard A1 Saquib Ali Lakhani A1 Friedhelm Hildebrandt A1 Mustafa K Khokha YR 2020 UL http://jmg.bmj.com/content/early/2020/07/05/jmedgenet-2019-106805.abstract AB 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.