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Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes
  1. Susanne Roosing1,
  2. Marta Romani2,
  3. Mala Isrie3,
  4. Rasim Ozgur Rosti4,
  5. Alessia Micalizzi2,5,
  6. Damir Musaev4,
  7. Tommaso Mazza2,
  8. Lihadh Al-gazali6,
  9. Umut Altunoglu7,
  10. Eugen Boltshauser8,
  11. Stefano D'Arrigo9,
  12. Bart De Keersmaecker10,11,
  13. Hülya Kayserili12,
  14. Sarah Brandenberger13,
  15. Ichraf Kraoua14,
  16. Paul R Mark13,
  17. Trudy McKanna13,
  18. Joachim Van Keirsbilck10,
  19. Philippe Moerman15,
  20. Andrea Poretti8,16,
  21. Ratna Puri17,
  22. Hilde Van Esch3,
  23. Joseph G Gleeson1,4,18,
  24. Enza Maria Valente19
  1. 1Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA
  2. 2IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy
  3. 3Department of Human Genetics, Laboratory for the Genetics of Cognition, Center for Human Genetics, KU Leuven, Belgium
  4. 4Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA
  5. 5Department of Biological and Environmental Science, University of Messina, Messina, Italy
  6. 6Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
  7. 7Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey
  8. 8Division of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland
  9. 9Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
  10. 10Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium
  11. 11Department of Obstetrics and Gynecology, AZ Groeninge, Kortrijk, Belgium
  12. 12Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey
  13. 13Spectrum Health Medical Genetics, Grand Rapids, Michigan, USA
  14. 14Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology of Tunis, La Rabta, Tunisia
  15. 15Department of Pathology, University Hospitals Leuven, Leuven, Belgium
  16. 16Section of Pediatric Neuroradiology, Division of Pediatric Radiology, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
  17. 17Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India
  18. 18Neurogenetics Laboratory, Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
  19. 19Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy
  1. Correspondence to Professor Enza Maria Valente, Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, 84081, Baronissi (SA), Italy; enzamaria.valente{at}


Background Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene.

Methods Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes.

Results We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype.

Conclusion Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype–phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

  • Clinical genetics
  • Developmental
  • Genetics
  • Molecular genetics
  • Neurosciences

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See:

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