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

Susanne Roosing, Marta Romani, Mala Isrie, Rasim Ozgur Rosti, Alessia Micalizzi, Damir Musaev, Tommaso Mazza, Lihadh Al-gazali, Umut Altunoglu, Eugen Boltshauser, Stefano D'Arrigo, Bart De Keersmaecker, Hülya Kayserili, Sarah Brandenberger, Ichraf Kraoua, Paul R. Mark, Trudy McKanna, Joachim Van Keirsbilck, Philippe Moerman, Andrea PorettiRatna Puri, Hilde Van Esch, Joseph G. Gleeson, Enza Maria Valente

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of Medical Genetics
DOIs
Publication statusAccepted/In press - May 6 2016

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Phenotype
Mutation
Exome
Encephalocele
Fetus
Genes
Genetic Association Studies
Ciliopathies
Joubert syndrome 1
Tooth
Jeune syndrome
Meckel syndrome type 1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. / Roosing, Susanne; Romani, Marta; Isrie, Mala; Rosti, Rasim Ozgur; Micalizzi, Alessia; Musaev, Damir; Mazza, Tommaso; Al-gazali, Lihadh; Altunoglu, Umut; Boltshauser, Eugen; D'Arrigo, Stefano; De Keersmaecker, Bart; Kayserili, Hülya; Brandenberger, Sarah; Kraoua, Ichraf; Mark, Paul R.; McKanna, Trudy; Van Keirsbilck, Joachim; Moerman, Philippe; Poretti, Andrea; Puri, Ratna; Van Esch, Hilde; Gleeson, Joseph G.; Valente, Enza Maria.

In: Journal of Medical Genetics, 06.05.2016.

Research output: Contribution to journalArticle

Roosing, S, Romani, M, Isrie, M, Rosti, RO, 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, EM 2016, 'Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes', Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2016-103832
Roosing, Susanne ; Romani, Marta ; Isrie, Mala ; Rosti, Rasim Ozgur ; Micalizzi, Alessia ; Musaev, Damir ; Mazza, Tommaso ; Al-gazali, Lihadh ; Altunoglu, Umut ; Boltshauser, Eugen ; D'Arrigo, Stefano ; De Keersmaecker, Bart ; Kayserili, Hülya ; Brandenberger, Sarah ; Kraoua, Ichraf ; Mark, Paul R. ; McKanna, Trudy ; Van Keirsbilck, Joachim ; Moerman, Philippe ; Poretti, Andrea ; Puri, Ratna ; Van Esch, Hilde ; Gleeson, Joseph G. ; Valente, Enza Maria. / Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. In: Journal of Medical Genetics. 2016.
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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.",
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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

PY - 2016/5/6

Y1 - 2016/5/6

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.

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