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Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.
J Med Genet. 2016 09; 53(9):608-15.JM

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.

Authors+Show Affiliations

Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy.Department of Human Genetics, Laboratory for the Genetics of Cognition, Center for Human Genetics, KU Leuven, Belgium.Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA.IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy Department of Biological and Environmental Science, University of Messina, Messina, Italy.Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA.IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy.Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey.Division of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland.Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, AZ Groeninge, Kortrijk, Belgium.Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey.Spectrum Health Medical Genetics, Grand Rapids, Michigan, USA.Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology of Tunis, La Rabta, Tunisia.Spectrum Health Medical Genetics, Grand Rapids, Michigan, USA.Spectrum Health Medical Genetics, Grand Rapids, Michigan, USA.Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.Department of Pathology, University Hospitals Leuven, Leuven, Belgium.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.Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India.Department of Human Genetics, Laboratory for the Genetics of Cognition, Center for Human Genetics, KU Leuven, Belgium.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.Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27208211

Citation

Roosing, Susanne, et al. "Mutations in CEP120 Cause Joubert Syndrome as Well as Complex Ciliopathy Phenotypes." Journal of Medical Genetics, vol. 53, no. 9, 2016, pp. 608-15.
Roosing S, Romani M, Isrie M, et al. Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. J Med Genet. 2016;53(9):608-15.
Roosing, S., Romani, M., Isrie, M., Rosti, R. O., Micalizzi, A., Musaev, D., Mazza, T., Al-Gazali, L., Altunoglu, U., Boltshauser, E., D'Arrigo, S., De Keersmaecker, B., Kayserili, H., Brandenberger, S., Kraoua, I., Mark, P. R., McKanna, T., Van Keirsbilck, J., Moerman, P., ... Valente, E. M. (2016). Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. Journal of Medical Genetics, 53(9), 608-15. https://doi.org/10.1136/jmedgenet-2016-103832
Roosing S, et al. Mutations in CEP120 Cause Joubert Syndrome as Well as Complex Ciliopathy Phenotypes. J Med Genet. 2016;53(9):608-15. PubMed PMID: 27208211.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. AU - Roosing,Susanne, AU - Romani,Marta, AU - Isrie,Mala, AU - Rosti,Rasim Ozgur, AU - Micalizzi,Alessia, AU - Musaev,Damir, AU - Mazza,Tommaso, AU - Al-Gazali,Lihadh, AU - Altunoglu,Umut, AU - Boltshauser,Eugen, AU - D'Arrigo,Stefano, AU - De Keersmaecker,Bart, AU - Kayserili,Hülya, AU - Brandenberger,Sarah, AU - Kraoua,Ichraf, AU - Mark,Paul R, AU - McKanna,Trudy, AU - Van Keirsbilck,Joachim, AU - Moerman,Philippe, AU - Poretti,Andrea, AU - Puri,Ratna, AU - Van Esch,Hilde, AU - Gleeson,Joseph G, AU - Valente,Enza Maria, Y1 - 2016/05/06/ PY - 2016/02/10/received PY - 2016/04/02/accepted PY - 2016/5/22/entrez PY - 2016/5/22/pubmed PY - 2017/11/1/medline KW - Clinical genetics KW - Developmental KW - Genetics KW - Molecular genetics KW - Neurosciences SP - 608 EP - 15 JF - Journal of medical genetics JO - J. Med. Genet. VL - 53 IS - 9 N2 - 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. SN - 1468-6244 UR - https://www.unboundmedicine.com/medline/citation/27208211/Mutations_in_CEP120_cause_Joubert_syndrome_as_well_as_complex_ciliopathy_phenotypes_ L2 - http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=27208211 DB - PRIME DP - Unbound Medicine ER -