TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes

Julie C. Van De Weghe, Jessica L. Giordano, University of Washington Center for Mendelian Genomics, 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 MaroofianDan Doherty*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Article number100016
JournalHuman Genetics and Genomics Advances
Volume2
Issue number1
DOIs
Publication statusPublished - 14 Jan 2021

Bibliographical note

Acknowledgments:
We deeply thank the families who participated in this study. We also thank the Joubert syndrome and Related Disorder Foundation for referring families to the UW cohort. We would like to thank the contributors to MyGene2. This work was supported by the following: NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development U54HD083091 (Genetics Core and Sub-project 6849) to D.D., NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development 1K99HD100554-01 to J.C.V, NIH National Institute of Neurological Diseases and Stroke ( R01NS064077 to D.D.), private donations from families to D.D., NIH National Human Genome Research Institute and National Heart, Lung, and Blood Institute ( UM1 HG006493 and U24 HG008956 ) to M.J.B. and D.A.N., Columbia University internal funding to J.L.G., MRC Clinical Scientist fellowship ( MR/K010654/1 ) to A.M.W., Paediatric Research award ( Paed_RP_011_20170929 ) to A.M.W., Medical Research Council (MRC) ( MR/S01165X/1 and MR/S005021/1 ) to R.M., The Wellcome Trust (Synaptopathies Strategic Award, WT093205MA and WT104033AIA ) to R.M., and ongoing support from The Rosetree Trust , Ataxia UK , The MSA Trust , Brain Research UK , Sparks GOSH Charity , Muscular Dystrophy UK (MDUK), and Muscular Dystrophy Association (MDA USA) to R.M.

Publisher Copyright: © 2020 The Authors

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