From Whole Gene Deletion to Point Mutations of EP300-Positive Rubinstein-Taybi Patients: New Insights into the Mutational Spectrum and Peculiar Clinical Hallmarks

Gloria Negri, Pamela Magini, Donatella Milani, Patrizia Colapietro, Daniela Rusconi, Emanuela Scarano, Maria Teresa Bonati, Manuela Priolo, Milena Crippa, Laura Mazzanti, Anita Wischmeijer, Federica Tamburrino, Tommaso Pippucci, Palma Finelli, Lidia Larizza, Cristina Gervasini

Research output: Contribution to journalArticle

Abstract

Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by growth deficiency, skeletal abnormalities, dysmorphic features, and intellectual disability. Causative mutations in CREBBP and EP300 genes have been identified in ∼55% and ∼8% of affected individuals. To date, only 28 EP300 alterations in 29 RSTS clinically described patients have been reported. EP300 analysis of 22 CREBBP-negative RSTS patients from our cohort led us to identify six novel mutations: a 376-kb deletion depleting EP300 gene; an exons 17-19 deletion (c.(3141+1_3142-1)_(3590+1_3591-1)del/p.(Ile1047Serfs*30)); two stop mutations, (c.3829A>T/p.(Lys1277*) and c.4585C>T/p.(Arg1529*)); a splicing mutation (c.1878-12A>G/p.(Ala627Glnfs*11)), and a duplication (c.4640dupA/p.(Asn1547Lysfs*3)). All EP300-mutated individuals show a mild RSTS phenotype and peculiar findings including maternal gestosis, skin manifestation, especially nevi or keloids, back malformations, and a behavior predisposing to anxiety. Furthermore, the patient carrying the complete EP300 deletion does not show a markedly severe clinical picture, even if a more composite phenotype was noticed. By characterizing six novel EP300-mutated patients, this study provides further insights into the EP300-specific clinical presentation and expands the mutational repertoire including the first case of a whole gene deletion. These new data will enhance EP300-mutated cases identification highlighting distinctive features and will improve the clinical practice allowing a better genotype-phenotype correlation.

Original languageEnglish
Pages (from-to)175-83
Number of pages9
JournalHuman Mutation
Volume37
Issue number2
DOIs
Publication statusPublished - Feb 2016

Keywords

  • Adolescent
  • CREB-Binding Protein
  • Child
  • E1A-Associated p300 Protein
  • Female
  • Gene Expression
  • Genetic Association Studies
  • Genetic Variation
  • Genome, Human
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Mutation
  • Phenotype
  • Rubinstein-Taybi Syndrome
  • Sequence Analysis, DNA
  • Young Adult
  • Journal Article
  • Research Support, Non-U.S. Gov't

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    Negri, G., Magini, P., Milani, D., Colapietro, P., Rusconi, D., Scarano, E., Bonati, M. T., Priolo, M., Crippa, M., Mazzanti, L., Wischmeijer, A., Tamburrino, F., Pippucci, T., Finelli, P., Larizza, L., & Gervasini, C. (2016). From Whole Gene Deletion to Point Mutations of EP300-Positive Rubinstein-Taybi Patients: New Insights into the Mutational Spectrum and Peculiar Clinical Hallmarks. Human Mutation, 37(2), 175-83. https://doi.org/10.1002/humu.22922