Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Exploring genotype–phenotype correlations in CREBBP: comment on the literature and description of an additional patient with an atypical outcome

European Journal of Human Genetics volume 31, pages 975–976 (2023)Cite this article

Subjects

Rubinstein-Taybi syndrome (RTS) is a rare, mainly sporadic, autosomal dominant genetic disorder characterized by distinctive facial features, broad thumbs and toes, postnatal growth retardation, microcephaly, and a degree of intellectual disability [1]. Average IQ typically ranges between 35 and 50; however, cognitive outcomes are highly variable and rare affected individuals have been reported with intellect within the normal range [1]. Genetic variation in the cAMP response element-binding protein (CREB)-Binding Protein (CREBBP) gene is implicated in ~55–75% of RTS patients [2]. CREBBP encodes a transcription co-activator, which interacts with a large number of proteins. Frameshift, nonsense and missense, and splicing variants (listed in order of prevalence) have been described throughout the CREBBP gene and represent the majority of genetic variation responsible for RTS [2]. Approximately 17% of RTS patients with CREBBP variation have intragenic CREBBP deletions or whole gene deletions encompassing CREBBP [2].

To date, over 250 RTS-causing genetic variants have been identified in this gene (www.lovd.nl/CREBBP) and almost all of these variants are private [3]. Though rare, descriptions of patients with recurrent variants are a key tool to assess for genotype–phenotype correlations. Multiple CREBBP RTS cohorts have been characterized to identify possible genotype–phenotype correlations, but no statistically significant trends have been recognized as of yet [3,4,5,6,7]. A more severe lethal phenotype was associated with CREBBP deletion as part of a contiguous gene deletion syndrome [8], though this has not been consistently recapitulated in additional cohorts [4,5,6, 9, 10]. On the other hand, milder phenotypes have been reported when a CREBBP microdeletion exists in mosaic form and is also postulated to exist with missense variation falling outside of the histone acetyltransferase domain of CREBBP [6, 11]. However, a larger cohort of RTS patients did not identify any differences in prevalence or severity of clinical features for truncating versus single amino acid substitutions, nor for specific exonic locations [4]. This is considered separately from the known association between a phenotypically distinct condition, Menke–Hennekam syndrome (MKS) (OMIM #618332), with missense variation in exon 30 and 31 of CREBBP.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Stevens CA. Rubinstein-Taybi syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al. editors. GeneReviews®. Seattle, WA: University of Washington, Seattle; 2002. https://www.ncbi.nlm.nih.gov/books/NBK1526/.

  2. Van Gils J, Magdinier F, Fergelot P, Lacombe D. Rubinstein-Taybi syndrome: a model of epigenetic disorder. Genes (Basel). 2021;12:968.

    Article  PubMed  Google Scholar 

  3. Cross E, Duncan-Flavell PJ, Howarth RJ, Hobbs JI, Thomas NS, Bunyan DJ. Screening of a large Rubinstein-Taybi cohort identified many novel variants and emphasizes the importance of the CREBBP histone acetyltransferase domain. Am J Med Genet A. 2020;182:2508–20.

    Article  CAS  PubMed  Google Scholar 

  4. Perez-Grijalba V, Garcia-Oguiza A, Lopez M, Armstrong J, Garcia-Minaur S, Mesa-Latorre JM, et al. New insights into genetic variant spectrum and genotype-phenotype correlations of Rubinstein-Taybi syndrome in 39 CREBBP-positive patients. Mol Genet Genom Med. 2019;7:e972.

    CAS  Google Scholar 

  5. Fergelot P, Van Belzen M, Van Gils J, Afenjar A, Armour CM, Arveiler B, et al. Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations. Am J Med Genet A. 2016;170:3069–82.

    Article  CAS  PubMed  Google Scholar 

  6. Spena S, Milani D, Rusconi D, Negri G, Colapietro P, Elcioglu N, et al. Insights into genotype-phenotype correlations from CREBBP point mutation screening in a cohort of 46 Rubinstein-Taybi syndrome patients. Clin Genet. 2015;88:431–40.

    Article  CAS  PubMed  Google Scholar 

  7. Rusconi D, Negri G, Colapietro P, Picinelli C, Milani D, Spena S, et al. Characterization of 14 novel deletions underlying Rubinstein-Taybi syndrome: an update of the CREBBP deletion repertoire. Hum Genet. 2015;134:613–26.

    Article  CAS  PubMed  Google Scholar 

  8. Bartsch O, Rasi S, Delicado A, Dyack S, Neumann LM, Seemanova E, et al. Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome. Hum Genet. 2006;120:179–86.

    Article  CAS  PubMed  Google Scholar 

  9. Coupry I, Roudaut C, Stef M, Delrue MA, Marche M, Burgelin I, et al. Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome. J Med Genet. 2002;39:415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schorry EK, Keddache M, Lanphear N, Rubinstein JH, Srodulski S, Fletcher D, et al. Genotype-phenotype correlations in Rubinstein-Taybi syndrome. Am J Med Genet A. 2008;146A:2512–9.

    Article  CAS  PubMed  Google Scholar 

  11. Gervasini C, Castronovo P, Bentivegna A, Mottadelli F, Faravelli F, Giovannucci-Uzielli ML, et al. High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints. Genomics. 2007;90:567–73.

    Article  CAS  PubMed  Google Scholar 

  12. Banka S, Sayer R, Breen C, Barton S, Pavaine J, Sheppard SE, et al. Genotype-phenotype specificity in Menke-Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP. Am J Med Genet A. 2019;179:1058–62.

    Article  CAS  PubMed  Google Scholar 

  13. Menke LA, van Belzen MJ, Alders M, Cristofoli F, Study DDD, Ehmke N, et al. CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype. Am J Med Genet A. 2016;170:2681–93.

    Article  CAS  PubMed  Google Scholar 

  14. Menke LA, Study DDD, Gardeitchik T, Hammond P, Heimdal KR, Houge G, et al. Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome. Am J Med Genet A. 2018;176:862–76.

    Article  CAS  PubMed  Google Scholar 

  15. Nishi E, Takenouchi T, Miya F, Uehara T, Yanagi K, Hasegawa Y, et al. The novel and recurrent variants in exon 31 of CREBBP in Japanese patients with Menke-Hennekam syndrome. Am J Med Genet A. 2022;188:446–53.

    Article  CAS  PubMed  Google Scholar 

  16. Bartsch O, Locher K, Meinecke P, Kress W, Seemanova E, Wagner A, et al. Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP. J Med Genet. 2002;39:496–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chau KK, Zhang P, Urresti J, Amar M, Pramod AB, Chen J, et al. Full-length isoform transcriptome of the developing human brain provides further insights into autism. Cell Rep. 2021;36:109631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to our patient and parents for participating in this study.

Funding

No financial assistance was received in support of this study.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, CHEO, Ottawa, ON, Canada

    Krista M. Vincent & Gail E. Graham

Authors
  1. Krista M. Vincent
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gail E. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GEG planned, supervised the study, and performed clinical work. KMV drafted the manuscript and all authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Krista M. Vincent.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Informed consent was obtained from the patient and his parents. Institutional ethics approval is not required due to the descriptive nature of the case report.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vincent, K.M., Graham, G.E. Exploring genotype–phenotype correlations in CREBBP: comment on the literature and description of an additional patient with an atypical outcome. Eur J Hum Genet 31, 975–976 (2023). https://doi.org/10.1038/s41431-023-01385-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41431-023-01385-x

This article is cited by

Search

Advanced search

Quick links