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 - Keersmaecker, Bart De
AU - Kayserili, Hülya
AU - Brandenberger, Sarah
AU - Kraoua, Ichraf
AU - Mark, Paul R.
AU - McKanna, Trudy
AU - Keirsbilck, Joachim Van
AU - Moerman, Philippe
AU - Poretti, Andrea
AU - Puri, Ratna
AU - Esch, Hilde Van
AU - Gleeson, Joseph G.
AU - Valente, Enza Maria
N1 - Funding Information:
This work was supported the European Research Council (ERC Starting Grant 260888 to EMV), Telethon Foundation Italy (GGP13146 to EMV), NI H grants (R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101 to JGG); the Howard Hughes Medical Institute and Simons Foundation (to JGG) and Concerted Research Actions KULeuven GOA/12/015 and funding from the Belgian Science Policy Office Interuniversity Attraction Poles programme (IAP P7/43-BeMGI to HVE). HVE is a clinical investigator of FWO-Vlaanderen.
PY - 2016/9/1
Y1 - 2016/9/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84966525869&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84966525869&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2016-103832
DO - 10.1136/jmedgenet-2016-103832
M3 - Article
C2 - 27208211
AN - SCOPUS:84966525869
SN - 0022-2593
VL - 53
SP - 608
EP - 615
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 9
ER -