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 Poretti & 4 others Ratna Puri, Hilde Van Esch, Joseph G. Gleeson, Enza Maria Valente

Research output: Contribution to journalArticleAcademicpeer-review

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
Pages (from-to)608-615
Number of pages8
JournalJournal of Medical Genetics
Volume53
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

Cite this

Roosing, S., Romani, M., Isrie, M., Rosti, R. O., Micalizzi, A., Musaev, D., ... Valente, E. M. (2016). Mutations in cep120 cause joubert syndrome as well as complex ciliopathy phenotypes. Journal of Medical Genetics, 53(9), 608-615. 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 ; Keersmaecker, Bart De ; Kayserili, Hülya ; Brandenberger, Sarah ; Kraoua, Ichraf ; Mark, Paul R. ; McKanna, Trudy ; Keirsbilck, Joachim Van ; Moerman, Philippe ; Poretti, Andrea ; Puri, Ratna ; Esch, Hilde Van ; Gleeson, Joseph G. ; Valente, Enza Maria. / Mutations in cep120 cause joubert syndrome as well as complex ciliopathy phenotypes. In: Journal of Medical Genetics. 2016 ; Vol. 53, No. 9. pp. 608-615.
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title = "Mutations in cep120 cause joubert syndrome as well as complex ciliopathy phenotypes",
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.",
author = "Susanne Roosing and Marta Romani and Mala Isrie and Rosti, {Rasim Ozgur} and Alessia Micalizzi and Damir Musaev and Tommaso Mazza and Lihadh Al-gazali and Umut Altunoglu and Eugen Boltshauser and Stefano D'Arrigo and Keersmaecker, {Bart De} and H{\"u}lya Kayserili and Sarah Brandenberger and Ichraf Kraoua and Mark, {Paul R.} and Trudy McKanna and Keirsbilck, {Joachim Van} and Philippe Moerman and Andrea Poretti and Ratna Puri and Esch, {Hilde Van} and Gleeson, {Joseph G.} and Valente, {Enza Maria}",
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Roosing, S, Romani, M, Isrie, M, Rosti, RO, Micalizzi, A, Musaev, D, Mazza, T, Al-gazali, L, Altunoglu, U, Boltshauser, E, D'Arrigo, S, Keersmaecker, BD, Kayserili, H, Brandenberger, S, Kraoua, I, Mark, PR, McKanna, T, Keirsbilck, JV, Moerman, P, Poretti, A, Puri, R, Esch, HV, Gleeson, JG & Valente, EM 2016, 'Mutations in cep120 cause joubert syndrome as well as complex ciliopathy phenotypes' Journal of Medical Genetics, vol. 53, no. 9, pp. 608-615. https://doi.org/10.1136/jmedgenet-2016-103832

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; Keersmaecker, Bart De; Kayserili, Hülya; Brandenberger, Sarah; Kraoua, Ichraf; Mark, Paul R.; McKanna, Trudy; Keirsbilck, Joachim Van; Moerman, Philippe; Poretti, Andrea; Puri, Ratna; Esch, Hilde Van; Gleeson, Joseph G.; Valente, Enza Maria.

In: Journal of Medical Genetics, Vol. 53, No. 9, 01.09.2016, p. 608-615.

Research output: Contribution to journalArticleAcademicpeer-review

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

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.

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U2 - 10.1136/jmedgenet-2016-103832

DO - 10.1136/jmedgenet-2016-103832

M3 - Article

VL - 53

SP - 608

EP - 615

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 9

ER -