Analysis of mutations within the intron20 splice donor site of CREBBP in patients with and without classical RSTS

Johannes G. Dauwerse, Martine van Belzen, Arie van Haeringen, Gijs van Santen, Christian van de Lans, Elisa Rahikkala, Livia Garavelli, Martijn Breuning, Raoul Hennekam, Dorien Peters

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Abstract

Whole-exome sequencing of a patient with intellectual disability and without recognisable phenotype yielded a mutation in the intron20 splice donor site of CREBBP. Mutations at different positions within the same intron20 splice donor site were observed in three patients clinically suspected as having Rubinstein-Taybi syndrome (RSTS). All mutations were de novo and likely disease-causing. To investigate a putative difference in splicing between the patient without RSTS phenotype and the three patients with the RSTS phenotype, we analysed the effects of these mutations on splicing of the pre-mRNA of CREBBP. As no RNA of patients was available, we generated a new and improved exon-trap vector, pCDNAGHE, and tested the effect of the various mutations on splicing in vitro. All mutations lead to skipping of exon20. In one of the patients with an RSTS phenotype, there was also some normal splicing detectable. We conclude that the splicing pattern obtained by exon-trapping cannot explain the difference in phenotype between the patient without the RSTS phenotype and the patients with clinical RSTS. Patient or tissue-specific splice effects as well as modifying genes likely will explain the difference in phenotype.European Journal of Human Genetics advance online publication, 11 May 2016; doi:10.1038/ejhg.2016.47.

Original languageEnglish
JournalEuropean Journal of Human Genetics
DOIs
Publication statusAccepted/In press - May 11 2016

Fingerprint

Rubinstein-Taybi Syndrome
RNA Splice Sites
Mutation
Phenotype
Exons
Exome
RNA Precursors
Medical Genetics
Intellectual Disability
Publications
RNA

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Dauwerse, J. G., van Belzen, M., van Haeringen, A., van Santen, G., van de Lans, C., Rahikkala, E., ... Peters, D. (Accepted/In press). Analysis of mutations within the intron20 splice donor site of CREBBP in patients with and without classical RSTS. European Journal of Human Genetics. https://doi.org/10.1038/ejhg.2016.47

Analysis of mutations within the intron20 splice donor site of CREBBP in patients with and without classical RSTS. / Dauwerse, Johannes G.; van Belzen, Martine; van Haeringen, Arie; van Santen, Gijs; van de Lans, Christian; Rahikkala, Elisa; Garavelli, Livia; Breuning, Martijn; Hennekam, Raoul; Peters, Dorien.

In: European Journal of Human Genetics, 11.05.2016.

Research output: Contribution to journalArticle

Dauwerse, JG, van Belzen, M, van Haeringen, A, van Santen, G, van de Lans, C, Rahikkala, E, Garavelli, L, Breuning, M, Hennekam, R & Peters, D 2016, 'Analysis of mutations within the intron20 splice donor site of CREBBP in patients with and without classical RSTS', European Journal of Human Genetics. https://doi.org/10.1038/ejhg.2016.47
Dauwerse, Johannes G. ; van Belzen, Martine ; van Haeringen, Arie ; van Santen, Gijs ; van de Lans, Christian ; Rahikkala, Elisa ; Garavelli, Livia ; Breuning, Martijn ; Hennekam, Raoul ; Peters, Dorien. / Analysis of mutations within the intron20 splice donor site of CREBBP in patients with and without classical RSTS. In: European Journal of Human Genetics. 2016.
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