2. Academic Validation
  3. Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes

Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes

  • J Med Genet. 2016 Sep;53(9):608-15. doi: 10.1136/jmedgenet-2016-103832.
Susanne Roosing 1,  Marta Romani 2,  Mala Isrie 3,  Rasim Ozgur Rosti 4,  Alessia Micalizzi 5,  Damir Musaev 4,  Tommaso Mazza 2,  Lihadh Al-Gazali 6,  Umut Altunoglu 7,  Eugen Boltshauser 8,  Stefano D'Arrigo 9,  Bart De Keersmaecker 10,  Hülya Kayserili 11,  Sarah Brandenberger 12,  Ichraf Kraoua 13,  Paul R Mark 12,  Trudy McKanna 12,  Joachim Van Keirsbilck 14,  Philippe Moerman 15,  Andrea Poretti 16,  Ratna Puri 17,  Hilde Van Esch 3,  Joseph G Gleeson 18,  Enza Maria Valente 19
Affiliations

Affiliations

  • 1 Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
  • 2 IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy.
  • 3 Department of Human Genetics, Laboratory for the Genetics of Cognition, Center for Human Genetics, KU Leuven, Belgium.
  • 4 Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA.
  • 5 IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy Department of Biological and Environmental Science, University of Messina, Messina, Italy.
  • 6 Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
  • 7 Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey.
  • 8 Division of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland.
  • 9 Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • 10 Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, AZ Groeninge, Kortrijk, Belgium.
  • 11 Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey.
  • 12 Spectrum Health Medical Genetics, Grand Rapids, Michigan, USA.
  • 13 Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology of Tunis, La Rabta, Tunisia.
  • 14 Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.
  • 15 Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
  • 16 Division of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland Section 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 Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India.
  • 18 Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA Neurogenetics Laboratory, Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • 19 Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
PMID: 27208211 DOI: 10.1136/jmedgenet-2016-103832
Abstract

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.

Keywords

Clinical genetics; Developmental; Genetics; Molecular genetics; Neurosciences.

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