title: Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
authors.forename: Susanne
authors.identifier: 0000-0001-9038-0067
authors.initials: S
authors.lastname: Roosing
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Romani
authors.affiliation: Department of Human Genetics, Laboratory for the Genetics of Cognition, Center for Human Genetics, KU Leuven, Belgium.
authors.forename: Mala
authors.initials: M
authors.lastname: Isrie
authors.affiliation: Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA.
authors.forename: Rasim Ozgur
authors.initials: RO
authors.lastname: Rosti
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy Department of Biological and Environmental Science, University of Messina, Messina, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Micalizzi
authors.affiliation: Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA.
authors.forename: Damir
authors.initials: D
authors.lastname: Musaev
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mazza
authors.affiliation: Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.affiliation: Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey.
authors.forename: Umut
authors.initials: U
authors.lastname: Altunoglu
authors.affiliation: Division of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland.
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.affiliation: Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: D'Arrigo
authors.affiliation: Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, AZ Groeninge, Kortrijk, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: De Keersmaecker
authors.affiliation: Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey.
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Spectrum Health Medical Genetics, Grand Rapids, Michigan, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Brandenberger
authors.affiliation: Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology of Tunis, La Rabta, Tunisia.
authors.forename: Ichraf
authors.initials: I
authors.lastname: Kraoua
authors.affiliation: Spectrum Health Medical Genetics, Grand Rapids, Michigan, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Mark
authors.affiliation: Spectrum Health Medical Genetics, Grand Rapids, Michigan, USA.
authors.forename: Trudy
authors.initials: T
authors.lastname: McKanna
authors.affiliation: Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Joachim
authors.initials: J
authors.lastname: Van Keirsbilck
authors.affiliation: Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moerman
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Poretti
authors.affiliation: Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India.
authors.forename: Ratna
authors.initials: R
authors.lastname: Puri
authors.affiliation: Department of Human Genetics, Laboratory for the Genetics of Cognition, Center for Human Genetics, KU Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: 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.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.affiliation: Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002526:Cerebellar Diseases / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D000072661:Ciliopathies / Q000235:genetics; D004677:Encephalocele / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D009958:Orofaciodigital Syndromes / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000002:abnormalities*; D016415:Sequence Alignment
chemical_list: C586986:CEP120 protein, human; D018797:Cell Cycle Proteins
keywords: Clinical genetics; Developmental; Genetics; Molecular genetics; Neurosciences