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Characterization of 14 novel deletions underlying Rubinstein–Taybi syndrome: an update of the CREBBP deletion repertoire

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Abstract

Rubinstein–Taybi syndrome (RSTS) is a rare, clinically heterogeneous disorder characterized by cognitive impairment and several multiple congenital anomalies. The syndrome is caused by almost private point mutations in the CREBBP (~55 % of cases) and EP300 (~8 %) genes. The CREBBP mutational spectrum is variegated and characterized by point mutations (30–50 %) and deletions (~10 %). The latter are diverse in size and genomic position and remove either the whole CREBBP gene and its flanking regions or only an intragenic portion. Here, we report 14 novel CREBBP deletions ranging from single exons to the whole gene and flanking regions which were identified by applying complementary cytomolecular techniques: fluorescence in situ hybridization, multiplex ligation-dependent probe amplification and array comparative genome hybridization, to a large cohort of RSTS patients. Deletions involving CREBBP account for 23 % of our detected CREBBP mutations, making an important contribution to the mutational spectrum. Genotype–phenotype correlations revealed that patients with CREBBP deletions extending beyond this gene did not always have a more severe phenotype than patients harboring CREBBP point mutations, suggesting that neighboring genes play only a limited role in the etiopathogenesis of CREBBP-centerd contiguous gene syndrome. Accordingly, the extent of the deletion is not predictive of the severity of the clinical phenotype.

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Acknowledgments

We are grateful to the patients’ families for participating in this study and to the Italian RSTS Association “Una Vita Speciale” and Associazione Studio Malformazioni (ASM onlus) for supporting this study. We thank Dr. Franca Rossella for her technical support. We thank the Galliera Genetic Bank for establishing lymphoblastoid cell lines through the Italian Telethon project GTF4003. This research was approved by the Ethical Clinical Research Committee of the clinical centers involved in patient recruitment and clinical evaluation. Written informed consent was obtained from the patients’ parents.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Via A. di Rudinì, 8, 20142, Milan, Italy

    Daniela Rusconi, Gloria Negri, Patrizia Colapietro, Silvia Spena, Lidia Larizza & Cristina Gervasini

  2. Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy

    Chiara Picinelli, Palma Finelli & Lidia Larizza

  3. Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico, Milan, Italy

    Donatella Milani

  4. Neonatology and Neonatal Intensive Care Unit, Maternal and Child Department, Parma University, Parma, Italy

    Cinzia Magnani

  5. Department of Paediatrics, University of Torino, Turin, Italy

    Margherita Cirillo Silengo, Lorena Sorasio, Giovanni Battista Ferrero & Elisa Biamino

  6. Clinical Genetics, Department of Medical Genetics and Fetal Medicine, University Hospital of Olomouc, Olomouc, Czech Republic

    Vaclava Curtisova

  7. Genetica Medica, AORN A. Cardarelli, Naples, Italy

    Maria Luigia Cavaliere

  8. Genetica Medica, Ospedale “S. Maria della Misericordia”, Perugia, Italy

    Paolo Prontera & Gabriela Stangoni

  9. U.O. Malattie Metaboliche Genetica Medica Endocrinologia, P.O. Giovanni XXIII, A.O.U. Policlinico Consorziale, Bari, Italy

    Rita Fischetto

  10. Dipartimento Materno Infantile, Azienda Ospedali Riuniti Villa Sofia Cervello-Università di Palermo, Palermo, Italy

    Maria Piccione

  11. Department of Medical Sciences, University of Trieste, Trieste, Italy

    Paolo Gasparini

  12. Institute for Maternal and Child Health-IRCCS ‘Burlo Garofolo’, Trieste, Italy

    Paolo Gasparini

  13. Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, and IRP Città della Speranza, Padua, Italy

    Leonardo Salviati

  14. Department of Pediatrics, Università Milano Bicocca, Fondazione MBBM, San Gerardo Hospital, Monza, Italy

    Angelo Selicorni

  15. Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy

    Palma Finelli

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  1. Daniela Rusconi
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  2. Gloria Negri
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  21. Palma Finelli
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  22. Lidia Larizza
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  23. Cristina Gervasini
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Corresponding authors

Correspondence to Lidia Larizza or Cristina Gervasini.

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439_2015_1542_MOESM1_ESM.tiff

Molecular flowchart applied to our RSTS cohort. Molecular flowchart applied to our cohort by combining different techniques. The number of patients tested and identified carriers of CREBB deletions/point mutations or EP300 mutations are provided. (TIFF 1141 kb)

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Supplementary material 3 (DOCX 30 kb)

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Rusconi, D., Negri, G., Colapietro, P. et al. Characterization of 14 novel deletions underlying Rubinstein–Taybi syndrome: an update of the CREBBP deletion repertoire. Hum Genet 134, 613–626 (2015). https://doi.org/10.1007/s00439-015-1542-9

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