Enza Maria Valente^1,2,24, Clare V Logan^3,24, Soumaya Mougou-Zerelli^4,5,24, Jeong Ho Lee^6,24, Jennifer L Silhavy⁶, Francesco Brancati^1,7, Miriam Iannicelli¹, Lorena Travaglini¹, Sveva Romani¹, Barbara Illi¹, Matthew Adams³, Katarzyna Szymanska³, Annalisa Mazzotta¹, Ji Eun Lee⁶, Jerlyn C Tolentino⁶, Dominika Swistun⁶, Carmelo D Salpietro², Carmelo Fede², Stacey Gabriel⁸, Carsten Russ⁸, Kristian Cibulskis8, Carrie Sougnez⁸, Friedhelm Hildebrandt⁹, Edgar A Otto⁹, Susanne Held⁹, Bill H Diplas¹⁰, Erica E Davis¹⁰, Mario Mikula¹¹, Charles M Strom¹¹, Bruria Ben-Zeev¹², Dorit Lev¹³, Tally Lerman Sagie¹³, Marina Michelson¹³, Yuval Yaron¹⁴, Amanda Krause¹⁵, Eugen Boltshauser¹⁶, Nadia Elkhartoufi¹⁷, Joelle Roume¹⁸, Stavit Shalev¹⁹, Arnold Munnich^4,17, Sophie Saunier²⁰, Chris Inglehearn³, Ali Saad⁵, Adila Alkindy^21,23, Sophie Thomas⁴, Michel Vekemans^4,17, Bruno Dallapiccola²², Nicholas Katsanis¹⁰, Colin A Johnson^3,25, Tania Attie-Bitach^4,17,25 & Joseph G Gleeson^6,25

¹Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Italy. ²Department of Medical and Surgical Paediatric Sciences, University of Messina, Messina, Italy. ³Section of Ophthalmology and Neurosciences, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds, UK. ⁴Departement de Genetique, INSERM U781, Hopital Necker-Enfants Malades, Universite Paris Descartes, Paris, France. ⁵Service de Cytogenetique, Genetique Moleculaire et Biologie de la Reproduction, Hopital Farhat Hached, Sousse, Tunisia. ⁶Neurogenetics Laboratory, Institute for Genomic Medicine, Department of Neurosciences and Pediatrics, Howard Hughes Medical Institute, University of California, San Diego, California, USA. ⁷Department of Biomedical Sciences and Aging Research Center, Center for Excellence in Aging, G. d’Annunzio University Foundation, Chieti, Italy. ⁸Genome Sequencing and Analysis Program, Broad Institute, Cambridge, Massachusetts, USA. ⁹Department of Pediatrics, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA. ¹⁰Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA. ¹¹Quest Diagnostics Nichols Institute, San Juan Capistrano, California, USA. ¹²Safra Pediatric Hospital, Pediatric Neurology Unit, Sheba Medical Center, Ramat-Gan, Israel. ¹³Institute of Medical Genetics, Metabolic Neurogenetics Service, Wolfson Medical Center, Holon, Israel. ¹⁴Prenatal Diagnosis Unit, Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. ¹⁵Division of Human Genetics, National Health Laboratory Service, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. ¹⁶Department of Paediatric Neurology, University Children’s Hospital of Zurich, Zurich, Switzerland. ¹⁷Departement de Genetique, Hopital Necker-Enfants Malade, Assistance Publique Hopitaux de Paris (APHP), Paris, France. ¹⁸Genetique Medicale, CHI Poissy, Saint Germain en Laye, France. ¹⁹The Genetics Institute, Ha’Emek Medical Center, Afula, Israel. ²⁰INSERM U983, Hopital Necker-Enfants Malade, Universite Paris Descartes, Assistance Publique-Hopitaux de Paris,
Paris, France. ²¹University Hospital of Wales, Heath Park, Cardiff, UK. ²²Istituto di Ricovero e Cura a Carattere Scientifico “Bambino Gesu Hospital,” Rome, Italy. ²³Current address: Clinical Genetics, College of Medicine & Health Sciences, Sultan Qaboos University Hospital, Al-Khod, Muscat, Oman. ²⁴These authors contributed equally to the work. ²⁵These authors jointly directed the project. Correspondence should be addressed to J.G.G., E.M.V. , C.A.J. or T.A.-B.

Joubert syndrome (JBTS), related disorders (JSRDs) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n = 10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.