TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes
Julie C. Van De Weghe,
Jessica L. Giordano,
Inge B. Mathijssen,
Majid Mojarrad,
Dorien Lugtenberg,
Caitlin V. Miller,
Jennifer C. Dempsey,
Mahsa Sadat Asl Mohajeri,
Elizabeth van Leeuwen,
Eva Pajkrt,
Caroline C.W. Klaver,
Henry Houlden,
Atieh Eslahi,
Aoife M. Waters,
Michael J. Bamshad,
Deborah A. Nickerson,
Vimla S. Aggarwal,
Bert B.A. de Vries,
Reza Maroofian,
Dan Doherty
Affiliations
Julie C. Van De Weghe
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Jessica L. Giordano
Department of OB/GYN, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Inge B. Mathijssen
Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Majid Mojarrad
Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Genetic Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Genetic Center of Khorasan Razavi, Mashhad, Iran
Dorien Lugtenberg
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
Caitlin V. Miller
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Jennifer C. Dempsey
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Mahsa Sadat Asl Mohajeri
Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Elizabeth van Leeuwen
Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Eva Pajkrt
Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Caroline C.W. Klaver
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands
Henry Houlden
Department of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK
Atieh Eslahi
Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Aoife M. Waters
Great Ormond Street Hospital NHS Foundation Trust, London WC1N 1LE, UK
Michael J. Bamshad
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; University of Washington Center for Mendelian Genomics, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Deborah A. Nickerson
University of Washington Center for Mendelian Genomics, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Vimla S. Aggarwal
Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032 USA
Bert B.A. de Vries
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
Reza Maroofian
Department of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK
Dan Doherty
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98101 USA; Corresponding author
Summary: The Joubert-Meckel syndrome spectrum is a continuum of recessive ciliopathy conditions caused by primary cilium dysfunction. The primary cilium is a microtubule-based, antenna-like organelle that projects from the surface of most human cell types, allowing them to respond to extracellular signals. The cilium is partitioned from the cell body by the transition zone, a known hotspot for ciliopathy-related proteins. Despite years of Joubert syndrome (JBTS) gene discovery, the genetic cause cannot be identified in up to 30% of individuals with JBTS, depending on the cohort, sequencing method, and criteria for pathogenic variants. Using exome and targeted sequencing of 655 families with JBTS, we identified three individuals from two families harboring biallelic, rare, predicted-deleterious missense TMEM218 variants. Via MatchMaker Exchange, we identified biallelic TMEM218 variants in four additional families with ciliopathy phenotypes. Of note, four of the six families carry missense variants affecting the same highly conserved amino acid position 115. Clinical features included the molar tooth sign (N = 2), occipital encephalocele (N = 5, all fetuses), retinal dystrophy (N = 4, all living individuals), polycystic kidneys (N = 2), and polydactyly (N = 2), without liver involvement. Combined with existing functional data linking TMEM218 to ciliary transition zone function, our human genetic data make a strong case for TMEM218 dysfunction as a cause of ciliopathy phenotypes including JBTS with retinal dystrophy and Meckel syndrome. Identifying all genetic causes of the Joubert-Meckel spectrum enables diagnostic testing, prognostic and recurrence risk counseling, and medical monitoring, as well as work to delineate the underlying biological mechanisms and identify targets for future therapies.
