Expanding CEP290 mutational spectrumin ciliopathies

Lorena Travaglini, Francesco Brancati, Tania Attie-Bitach, Sophie Audollent, Enrico Bertini, Josseline Kaplan, Isabelle Perrault, Miriam Iannicelli, Brunella Mancuso, Luciana Rigoli, Jean Michel Rozet, Dominika Swistun, Jerlyn Tolentino, Bruno Dallapiccola, Joseph G. Gleeson, Enza Maria Valente, A. Zankl, R. Leventer, P. Grattan-Smith, A. Janecke & 147 others M. D'Hooghe, Y. Sznajer, R. Van Coster, L. Demerleir, K. Dias, C. Moco, A. Moreira, C. Ae Kim, G. Maegawa, D. Petkovic, G. M H Abdel-Salam, Alice Kamal Abd El Aleem, M. S. Zaki, I. Marti, S. Quijano-Roy, S. Sigaudy, P. De Lonlay, S. Romano, R. Touraine, M. Koenig, C. Lagier-Tourenne, J. Messer, P. Collignon, N. Wolf, H. Philippi, S. Kitsiou Tzeli, S. Halldorsson, J. Johannsdottir, P. Ludvigsson, S. R. Phadke, V. Udani, B. Stuart, A. Magee, D. Lev, M. Michelson, B. Ben-Zeev, R. Fischetto, F. Benedicenti, F. Stanzial, R. Borgatti, P. Accorsi, S. Battaglia, E. Fazzi, L. Giordano, L. Pinelli, L. Boccone, S. Bigoni, A. Ferlini, M. A. Donati, G. Caridi, M. T. Divizia, F. Faravelli, G. Ghiggeri, A. Pessagno, M. Briguglio, S. Briuglia, C. D. Salpietro, G. Tortorella, A. Adami, P. Castorina, F. Lalatta, G. Marra, D. Riva, B. Scelsa, L. Spaccini, G. Uziel, E. Del Giudice, A. M. Laverda, K. Ludwig, A. Permunian, A. Suppiej, S. Signorini, C. Uggetti, R. Battini, M. Di Giacomo, M. R. Cilio, M. L. Di Sabato, V. Leuzzi, P. Parisi, M. Pollazzon, M. Silengo, R. De Vescovi, D. Greco, C. Romano, M. Cazzagon, A. Simonati, A. A. Al-Tawari, L. Bastaki, A. Mégarbané, V. Sabolic Avramovska, M. M. De Jong, P. Stromme, R. Koul, A. Rajab, M. Azam, C. Barbot, L. Martorell Sampol, B. Rodriguez, I. Pascual-Castroviejo, S. Teber, B. Anlar, S. Comu, E. Karaca, H. Kayserili, A. Yüksel, M. Akcakus, L. Al Gazali, L. Sztriha, D. Nicholl, C. G. Woods, C. Bennett, J. Hurst, E. Sheridan, A. Barnicoat, R. Hennekam, M. Lees, E. Blair, S. Bernes, H. Sanchez, A. E. Clark, E. DeMarco, C. Donahue, E. Sherr, J. Hahn, T. D. Sanger, T. E. Gallager, W. B. Dobyns, C. Daugherty, K. S. Krishnamoorthy, D. Sarco, C. A. Walsh, T. McKanna, J. Milisa, W. K. Chung, D. C. De Vivo, H. Raynes, R. Schubert, A. Seward, D. G. Brooks, A. Goldstein, J. Caldwell, E. Finsecke, B. L. Maria, K. Holden, R. P. Cruse, K. J. Swoboda, D. Viskochil

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/ MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C -terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

Original languageEnglish
Pages (from-to)2173-2180
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume149
Issue number10
DOIs
Publication statusPublished - Oct 2009
Externally publishedYes

Fingerprint

Leber Congenital Amaurosis
Mutation
Cilia
Genes
Exons
Alleles
Messenger RNA
Ciliopathies
DNA
Joubert syndrome 1
Proteins
Meckel syndrome type 1

Keywords

  • CEP290
  • Genomic rearrangement
  • Joubert syndrome and related disorders
  • Meckel syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Travaglini, L., Brancati, F., Attie-Bitach, T., Audollent, S., Bertini, E., Kaplan, J., ... Viskochil, D. (2009). Expanding CEP290 mutational spectrumin ciliopathies. American Journal of Medical Genetics, Part A, 149(10), 2173-2180. https://doi.org/10.1002/ajmg.a.33025

Expanding CEP290 mutational spectrumin ciliopathies. / Travaglini, Lorena; Brancati, Francesco; Attie-Bitach, Tania; Audollent, Sophie; Bertini, Enrico; Kaplan, Josseline; Perrault, Isabelle; Iannicelli, Miriam; Mancuso, Brunella; Rigoli, Luciana; Rozet, Jean Michel; Swistun, Dominika; Tolentino, Jerlyn; Dallapiccola, Bruno; Gleeson, Joseph G.; Valente, Enza Maria; Zankl, A.; Leventer, R.; Grattan-Smith, P.; Janecke, A.; D'Hooghe, M.; Sznajer, Y.; Van Coster, R.; Demerleir, L.; Dias, K.; Moco, C.; Moreira, A.; Ae Kim, C.; Maegawa, G.; Petkovic, D.; Abdel-Salam, G. M H; Kamal Abd El Aleem, Alice; Zaki, M. S.; Marti, I.; Quijano-Roy, S.; Sigaudy, S.; De Lonlay, P.; Romano, S.; Touraine, R.; Koenig, M.; Lagier-Tourenne, C.; Messer, J.; Collignon, P.; Wolf, N.; Philippi, H.; Kitsiou Tzeli, S.; Halldorsson, S.; Johannsdottir, J.; Ludvigsson, P.; Phadke, S. R.; Udani, V.; Stuart, B.; Magee, A.; Lev, D.; Michelson, M.; Ben-Zeev, B.; Fischetto, R.; Benedicenti, F.; Stanzial, F.; Borgatti, R.; Accorsi, P.; Battaglia, S.; Fazzi, E.; Giordano, L.; Pinelli, L.; Boccone, L.; Bigoni, S.; Ferlini, A.; Donati, M. A.; Caridi, G.; Divizia, M. T.; Faravelli, F.; Ghiggeri, G.; Pessagno, A.; Briguglio, M.; Briuglia, S.; Salpietro, C. D.; Tortorella, G.; Adami, A.; Castorina, P.; Lalatta, F.; Marra, G.; Riva, D.; Scelsa, B.; Spaccini, L.; Uziel, G.; Del Giudice, E.; Laverda, A. M.; Ludwig, K.; Permunian, A.; Suppiej, A.; Signorini, S.; Uggetti, C.; Battini, R.; Di Giacomo, M.; Cilio, M. R.; Di Sabato, M. L.; Leuzzi, V.; Parisi, P.; Pollazzon, M.; Silengo, M.; De Vescovi, R.; Greco, D.; Romano, C.; Cazzagon, M.; Simonati, A.; Al-Tawari, A. A.; Bastaki, L.; Mégarbané, A.; Sabolic Avramovska, V.; De Jong, M. M.; Stromme, P.; Koul, R.; Rajab, A.; Azam, M.; Barbot, C.; Martorell Sampol, L.; Rodriguez, B.; Pascual-Castroviejo, I.; Teber, S.; Anlar, B.; Comu, S.; Karaca, E.; Kayserili, H.; Yüksel, A.; Akcakus, M.; Al Gazali, L.; Sztriha, L.; Nicholl, D.; Woods, C. G.; Bennett, C.; Hurst, J.; Sheridan, E.; Barnicoat, A.; Hennekam, R.; Lees, M.; Blair, E.; Bernes, S.; Sanchez, H.; Clark, A. E.; DeMarco, E.; Donahue, C.; Sherr, E.; Hahn, J.; Sanger, T. D.; Gallager, T. E.; Dobyns, W. B.; Daugherty, C.; Krishnamoorthy, K. S.; Sarco, D.; Walsh, C. A.; McKanna, T.; Milisa, J.; Chung, W. K.; De Vivo, D. C.; Raynes, H.; Schubert, R.; Seward, A.; Brooks, D. G.; Goldstein, A.; Caldwell, J.; Finsecke, E.; Maria, B. L.; Holden, K.; Cruse, R. P.; Swoboda, K. J.; Viskochil, D.

In: American Journal of Medical Genetics, Part A, Vol. 149, No. 10, 10.2009, p. 2173-2180.

Research output: Contribution to journalArticle

Travaglini, L, Brancati, F, Attie-Bitach, T, Audollent, S, Bertini, E, Kaplan, J, Perrault, I, Iannicelli, M, Mancuso, B, Rigoli, L, Rozet, JM, Swistun, D, Tolentino, J, Dallapiccola, B, Gleeson, JG, Valente, EM, Zankl, A, Leventer, R, Grattan-Smith, P, Janecke, A, D'Hooghe, M, Sznajer, Y, Van Coster, R, Demerleir, L, Dias, K, Moco, C, Moreira, A, Ae Kim, C, Maegawa, G, Petkovic, D, Abdel-Salam, GMH, Kamal Abd El Aleem, A, Zaki, MS, Marti, I, Quijano-Roy, S, Sigaudy, S, De Lonlay, P, Romano, S, Touraine, R, Koenig, M, Lagier-Tourenne, C, Messer, J, Collignon, P, Wolf, N, Philippi, H, Kitsiou Tzeli, S, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Phadke, SR, Udani, V, Stuart, B, Magee, A, Lev, D, Michelson, M, Ben-Zeev, B, Fischetto, R, Benedicenti, F, Stanzial, F, Borgatti, R, Accorsi, P, Battaglia, S, Fazzi, E, Giordano, L, Pinelli, L, Boccone, L, Bigoni, S, Ferlini, A, Donati, MA, Caridi, G, Divizia, MT, Faravelli, F, Ghiggeri, G, Pessagno, A, Briguglio, M, Briuglia, S, Salpietro, CD, Tortorella, G, Adami, A, Castorina, P, Lalatta, F, Marra, G, Riva, D, Scelsa, B, Spaccini, L, Uziel, G, Del Giudice, E, Laverda, AM, Ludwig, K, Permunian, A, Suppiej, A, Signorini, S, Uggetti, C, Battini, R, Di Giacomo, M, Cilio, MR, Di Sabato, ML, Leuzzi, V, Parisi, P, Pollazzon, M, Silengo, M, De Vescovi, R, Greco, D, Romano, C, Cazzagon, M, Simonati, A, Al-Tawari, AA, Bastaki, L, Mégarbané, A, Sabolic Avramovska, V, De Jong, MM, Stromme, P, Koul, R, Rajab, A, Azam, M, Barbot, C, Martorell Sampol, L, Rodriguez, B, Pascual-Castroviejo, I, Teber, S, Anlar, B, Comu, S, Karaca, E, Kayserili, H, Yüksel, A, Akcakus, M, Al Gazali, L, Sztriha, L, Nicholl, D, Woods, CG, Bennett, C, Hurst, J, Sheridan, E, Barnicoat, A, Hennekam, R, Lees, M, Blair, E, Bernes, S, Sanchez, H, Clark, AE, DeMarco, E, Donahue, C, Sherr, E, Hahn, J, Sanger, TD, Gallager, TE, Dobyns, WB, Daugherty, C, Krishnamoorthy, KS, Sarco, D, Walsh, CA, McKanna, T, Milisa, J, Chung, WK, De Vivo, DC, Raynes, H, Schubert, R, Seward, A, Brooks, DG, Goldstein, A, Caldwell, J, Finsecke, E, Maria, BL, Holden, K, Cruse, RP, Swoboda, KJ & Viskochil, D 2009, 'Expanding CEP290 mutational spectrumin ciliopathies', American Journal of Medical Genetics, Part A, vol. 149, no. 10, pp. 2173-2180. https://doi.org/10.1002/ajmg.a.33025
Travaglini L, Brancati F, Attie-Bitach T, Audollent S, Bertini E, Kaplan J et al. Expanding CEP290 mutational spectrumin ciliopathies. American Journal of Medical Genetics, Part A. 2009 Oct;149(10):2173-2180. https://doi.org/10.1002/ajmg.a.33025
Travaglini, Lorena ; Brancati, Francesco ; Attie-Bitach, Tania ; Audollent, Sophie ; Bertini, Enrico ; Kaplan, Josseline ; Perrault, Isabelle ; Iannicelli, Miriam ; Mancuso, Brunella ; Rigoli, Luciana ; Rozet, Jean Michel ; Swistun, Dominika ; Tolentino, Jerlyn ; Dallapiccola, Bruno ; Gleeson, Joseph G. ; Valente, Enza Maria ; Zankl, A. ; Leventer, R. ; Grattan-Smith, P. ; Janecke, A. ; D'Hooghe, M. ; Sznajer, Y. ; Van Coster, R. ; Demerleir, L. ; Dias, K. ; Moco, C. ; Moreira, A. ; Ae Kim, C. ; Maegawa, G. ; Petkovic, D. ; Abdel-Salam, G. M H ; Kamal Abd El Aleem, Alice ; Zaki, M. S. ; Marti, I. ; Quijano-Roy, S. ; Sigaudy, S. ; De Lonlay, P. ; Romano, S. ; Touraine, R. ; Koenig, M. ; Lagier-Tourenne, C. ; Messer, J. ; Collignon, P. ; Wolf, N. ; Philippi, H. ; Kitsiou Tzeli, S. ; Halldorsson, S. ; Johannsdottir, J. ; Ludvigsson, P. ; Phadke, S. R. ; Udani, V. ; Stuart, B. ; Magee, A. ; Lev, D. ; Michelson, M. ; Ben-Zeev, B. ; Fischetto, R. ; Benedicenti, F. ; Stanzial, F. ; Borgatti, R. ; Accorsi, P. ; Battaglia, S. ; Fazzi, E. ; Giordano, L. ; Pinelli, L. ; Boccone, L. ; Bigoni, S. ; Ferlini, A. ; Donati, M. A. ; Caridi, G. ; Divizia, M. T. ; Faravelli, F. ; Ghiggeri, G. ; Pessagno, A. ; Briguglio, M. ; Briuglia, S. ; Salpietro, C. D. ; Tortorella, G. ; Adami, A. ; Castorina, P. ; Lalatta, F. ; Marra, G. ; Riva, D. ; Scelsa, B. ; Spaccini, L. ; Uziel, G. ; Del Giudice, E. ; Laverda, A. M. ; Ludwig, K. ; Permunian, A. ; Suppiej, A. ; Signorini, S. ; Uggetti, C. ; Battini, R. ; Di Giacomo, M. ; Cilio, M. R. ; Di Sabato, M. L. ; Leuzzi, V. ; Parisi, P. ; Pollazzon, M. ; Silengo, M. ; De Vescovi, R. ; Greco, D. ; Romano, C. ; Cazzagon, M. ; Simonati, A. ; Al-Tawari, A. A. ; Bastaki, L. ; Mégarbané, A. ; Sabolic Avramovska, V. ; De Jong, M. M. ; Stromme, P. ; Koul, R. ; Rajab, A. ; Azam, M. ; Barbot, C. ; Martorell Sampol, L. ; Rodriguez, B. ; Pascual-Castroviejo, I. ; Teber, S. ; Anlar, B. ; Comu, S. ; Karaca, E. ; Kayserili, H. ; Yüksel, A. ; Akcakus, M. ; Al Gazali, L. ; Sztriha, L. ; Nicholl, D. ; Woods, C. G. ; Bennett, C. ; Hurst, J. ; Sheridan, E. ; Barnicoat, A. ; Hennekam, R. ; Lees, M. ; Blair, E. ; Bernes, S. ; Sanchez, H. ; Clark, A. E. ; DeMarco, E. ; Donahue, C. ; Sherr, E. ; Hahn, J. ; Sanger, T. D. ; Gallager, T. E. ; Dobyns, W. B. ; Daugherty, C. ; Krishnamoorthy, K. S. ; Sarco, D. ; Walsh, C. A. ; McKanna, T. ; Milisa, J. ; Chung, W. K. ; De Vivo, D. C. ; Raynes, H. ; Schubert, R. ; Seward, A. ; Brooks, D. G. ; Goldstein, A. ; Caldwell, J. ; Finsecke, E. ; Maria, B. L. ; Holden, K. ; Cruse, R. P. ; Swoboda, K. J. ; Viskochil, D. / Expanding CEP290 mutational spectrumin ciliopathies. In: American Journal of Medical Genetics, Part A. 2009 ; Vol. 149, No. 10. pp. 2173-2180.
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title = "Expanding CEP290 mutational spectrumin ciliopathies",
abstract = "Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/ MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C -terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.",
keywords = "CEP290, Genomic rearrangement, Joubert syndrome and related disorders, Meckel syndrome",
author = "Lorena Travaglini and Francesco Brancati and Tania Attie-Bitach and Sophie Audollent and Enrico Bertini and Josseline Kaplan and Isabelle Perrault and Miriam Iannicelli and Brunella Mancuso and Luciana Rigoli and Rozet, {Jean Michel} and Dominika Swistun and Jerlyn Tolentino and Bruno Dallapiccola and Gleeson, {Joseph G.} and Valente, {Enza Maria} and A. Zankl and R. Leventer and P. Grattan-Smith and A. Janecke and M. D'Hooghe and Y. Sznajer and {Van Coster}, R. and L. Demerleir and K. Dias and C. Moco and A. Moreira and {Ae Kim}, C. and G. Maegawa and D. Petkovic and Abdel-Salam, {G. M H} and {Kamal Abd El Aleem}, Alice and Zaki, {M. S.} and I. Marti and S. Quijano-Roy and S. Sigaudy and {De Lonlay}, P. and S. Romano and R. Touraine and M. Koenig and C. Lagier-Tourenne and J. Messer and P. Collignon and N. Wolf and H. Philippi and {Kitsiou Tzeli}, S. and S. Halldorsson and J. Johannsdottir and P. Ludvigsson and Phadke, {S. R.} and V. Udani and B. Stuart and A. Magee and D. Lev and M. Michelson and B. Ben-Zeev and R. Fischetto and F. Benedicenti and F. Stanzial and R. Borgatti and P. Accorsi and S. Battaglia and E. Fazzi and L. Giordano and L. Pinelli and L. Boccone and S. Bigoni and A. Ferlini and Donati, {M. A.} and G. Caridi and Divizia, {M. T.} and F. Faravelli and G. Ghiggeri and A. Pessagno and M. Briguglio and S. Briuglia and Salpietro, {C. D.} and G. Tortorella and A. Adami and P. Castorina and F. Lalatta and G. Marra and D. Riva and B. Scelsa and L. Spaccini and G. Uziel and {Del Giudice}, E. and Laverda, {A. M.} and K. Ludwig and A. Permunian and A. Suppiej and S. Signorini and C. Uggetti and R. Battini and {Di Giacomo}, M. and Cilio, {M. R.} and {Di Sabato}, {M. L.} and V. Leuzzi and P. Parisi and M. Pollazzon and M. Silengo and {De Vescovi}, R. and D. Greco and C. Romano and M. Cazzagon and A. Simonati and Al-Tawari, {A. A.} and L. Bastaki and A. M{\'e}garban{\'e} and {Sabolic Avramovska}, V. and {De Jong}, {M. M.} and P. Stromme and R. Koul and A. Rajab and M. Azam and C. Barbot and {Martorell Sampol}, L. and B. Rodriguez and I. Pascual-Castroviejo and S. Teber and B. Anlar and S. Comu and E. Karaca and H. Kayserili and A. Y{\"u}ksel and M. Akcakus and {Al Gazali}, L. and L. Sztriha and D. Nicholl and Woods, {C. G.} and C. Bennett and J. Hurst and E. Sheridan and A. Barnicoat and R. Hennekam and M. Lees and E. Blair and S. Bernes and H. Sanchez and Clark, {A. E.} and E. DeMarco and C. Donahue and E. Sherr and J. Hahn and Sanger, {T. D.} and Gallager, {T. E.} and Dobyns, {W. B.} and C. Daugherty and Krishnamoorthy, {K. S.} and D. Sarco and Walsh, {C. A.} and T. McKanna and J. Milisa and Chung, {W. K.} and {De Vivo}, {D. C.} and H. Raynes and R. Schubert and A. Seward and Brooks, {D. G.} and A. Goldstein and J. Caldwell and E. Finsecke and Maria, {B. L.} and K. Holden and Cruse, {R. P.} and Swoboda, {K. J.} and D. Viskochil",
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doi = "10.1002/ajmg.a.33025",
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volume = "149",
pages = "2173--2180",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
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TY - JOUR

T1 - Expanding CEP290 mutational spectrumin ciliopathies

AU - Travaglini, Lorena

AU - Brancati, Francesco

AU - Attie-Bitach, Tania

AU - Audollent, Sophie

AU - Bertini, Enrico

AU - Kaplan, Josseline

AU - Perrault, Isabelle

AU - Iannicelli, Miriam

AU - Mancuso, Brunella

AU - Rigoli, Luciana

AU - Rozet, Jean Michel

AU - Swistun, Dominika

AU - Tolentino, Jerlyn

AU - Dallapiccola, Bruno

AU - Gleeson, Joseph G.

AU - Valente, Enza Maria

AU - Zankl, A.

AU - Leventer, R.

AU - Grattan-Smith, P.

AU - Janecke, A.

AU - D'Hooghe, M.

AU - Sznajer, Y.

AU - Van Coster, R.

AU - Demerleir, L.

AU - Dias, K.

AU - Moco, C.

AU - Moreira, A.

AU - Ae Kim, C.

AU - Maegawa, G.

AU - Petkovic, D.

AU - Abdel-Salam, G. M H

AU - Kamal Abd El Aleem, Alice

AU - Zaki, M. S.

AU - Marti, I.

AU - Quijano-Roy, S.

AU - Sigaudy, S.

AU - De Lonlay, P.

AU - Romano, S.

AU - Touraine, R.

AU - Koenig, M.

AU - Lagier-Tourenne, C.

AU - Messer, J.

AU - Collignon, P.

AU - Wolf, N.

AU - Philippi, H.

AU - Kitsiou Tzeli, S.

AU - Halldorsson, S.

AU - Johannsdottir, J.

AU - Ludvigsson, P.

AU - Phadke, S. R.

AU - Udani, V.

AU - Stuart, B.

AU - Magee, A.

AU - Lev, D.

AU - Michelson, M.

AU - Ben-Zeev, B.

AU - Fischetto, R.

AU - Benedicenti, F.

AU - Stanzial, F.

AU - Borgatti, R.

AU - Accorsi, P.

AU - Battaglia, S.

AU - Fazzi, E.

AU - Giordano, L.

AU - Pinelli, L.

AU - Boccone, L.

AU - Bigoni, S.

AU - Ferlini, A.

AU - Donati, M. A.

AU - Caridi, G.

AU - Divizia, M. T.

AU - Faravelli, F.

AU - Ghiggeri, G.

AU - Pessagno, A.

AU - Briguglio, M.

AU - Briuglia, S.

AU - Salpietro, C. D.

AU - Tortorella, G.

AU - Adami, A.

AU - Castorina, P.

AU - Lalatta, F.

AU - Marra, G.

AU - Riva, D.

AU - Scelsa, B.

AU - Spaccini, L.

AU - Uziel, G.

AU - Del Giudice, E.

AU - Laverda, A. M.

AU - Ludwig, K.

AU - Permunian, A.

AU - Suppiej, A.

AU - Signorini, S.

AU - Uggetti, C.

AU - Battini, R.

AU - Di Giacomo, M.

AU - Cilio, M. R.

AU - Di Sabato, M. L.

AU - Leuzzi, V.

AU - Parisi, P.

AU - Pollazzon, M.

AU - Silengo, M.

AU - De Vescovi, R.

AU - Greco, D.

AU - Romano, C.

AU - Cazzagon, M.

AU - Simonati, A.

AU - Al-Tawari, A. A.

AU - Bastaki, L.

AU - Mégarbané, A.

AU - Sabolic Avramovska, V.

AU - De Jong, M. M.

AU - Stromme, P.

AU - Koul, R.

AU - Rajab, A.

AU - Azam, M.

AU - Barbot, C.

AU - Martorell Sampol, L.

AU - Rodriguez, B.

AU - Pascual-Castroviejo, I.

AU - Teber, S.

AU - Anlar, B.

AU - Comu, S.

AU - Karaca, E.

AU - Kayserili, H.

AU - Yüksel, A.

AU - Akcakus, M.

AU - Al Gazali, L.

AU - Sztriha, L.

AU - Nicholl, D.

AU - Woods, C. G.

AU - Bennett, C.

AU - Hurst, J.

AU - Sheridan, E.

AU - Barnicoat, A.

AU - Hennekam, R.

AU - Lees, M.

AU - Blair, E.

AU - Bernes, S.

AU - Sanchez, H.

AU - Clark, A. E.

AU - DeMarco, E.

AU - Donahue, C.

AU - Sherr, E.

AU - Hahn, J.

AU - Sanger, T. D.

AU - Gallager, T. E.

AU - Dobyns, W. B.

AU - Daugherty, C.

AU - Krishnamoorthy, K. S.

AU - Sarco, D.

AU - Walsh, C. A.

AU - McKanna, T.

AU - Milisa, J.

AU - Chung, W. K.

AU - De Vivo, D. C.

AU - Raynes, H.

AU - Schubert, R.

AU - Seward, A.

AU - Brooks, D. G.

AU - Goldstein, A.

AU - Caldwell, J.

AU - Finsecke, E.

AU - Maria, B. L.

AU - Holden, K.

AU - Cruse, R. P.

AU - Swoboda, K. J.

AU - Viskochil, D.

PY - 2009/10

Y1 - 2009/10

N2 - Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/ MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C -terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

AB - Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/ MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C -terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

KW - CEP290

KW - Genomic rearrangement

KW - Joubert syndrome and related disorders

KW - Meckel syndrome

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U2 - 10.1002/ajmg.a.33025

DO - 10.1002/ajmg.a.33025

M3 - Article

VL - 149

SP - 2173

EP - 2180

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 10

ER -