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

TitleMutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.
Publication TypeJournal Article
Year of Publication2016
AuthorsRoosing, S, Romani, M, Isrie, M, Rosti, ROzgur, 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, PR, McKanna, T, Van Keirsbilck, J, Moerman, P, Poretti, A, Puri, R, Van Esch, H, Gleeson, JG, Valente, EMaria
JournalJ Med Genet
Date Published2016 09
KeywordsAbnormalities, Multiple, Amino Acid Sequence, Cell Cycle Proteins, Cerebellar Diseases, Cerebellum, Child, Ciliopathies, Encephalocele, Eye Abnormalities, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Kidney Diseases, Cystic, Male, Mutation, Mutation Rate, Orofaciodigital Syndromes, Pedigree, Phenotype, Retina, Sequence Alignment

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.

Alternate JournalJ. Med. Genet.
PubMed ID27208211
PubMed Central IDPMC5013089
Grant List260888 / / European Research Council / International
U54 HG003067 / HG / NHGRI NIH HHS / United States
P30 NS047101 / NS / NINDS NIH HHS / United States
R01 NS041537 / NS / NINDS NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
GGP13146 / / Telethon / Italy
R01 NS052455 / NS / NINDS NIH HHS / United States
P01 HD070494 / HD / NICHD NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States