Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein–Taybi syndrome

Leonie A. Menke*, Thatjana Gardeitchik, Peter Hammond, Ketil R. Heimdal, Gunnar Houge, Sophia B. Hufnagel, Jianling Ji, Stefan Johansson, Sarina G. Kant, Esther Kinning, Eyby L. Leon, Ruth Newbury-Ecob, Stefano Paolacci, Rolph Pfundt, Nicola K. Ragge, Tuula Rinne, Claudia Ruivenkamp, Sulagna C. Saitta, Yu Sun, Marco TartagliaPaulien A. Terhal, Anthony J. van Essen, Magnus D. Vigeland, Bing Xiao, Raoul C. Hennekam, The DDD study

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

24 Citations (Scopus)


In 2016, we described that missense variants in parts of exons 30 and 31 of CREBBP can cause a phenotype that differs from Rubinstein–Taybi syndrome (RSTS). Here we report on another 11 patients with variants in this region of CREBBP (between bp 5,128 and 5,614) and two with variants in the homologous region of EP300. None of the patients show characteristics typical for RSTS. The variants were detected by exome sequencing using a panel for intellectual disability in all but one individual, in whom Sanger sequencing was performed upon clinical recognition of the entity. The main characteristics of the patients are developmental delay (90%), autistic behavior (65%), short stature (42%), and microcephaly (43%). Medical problems include feeding problems (75%), vision (50%), and hearing (54%) impairments, recurrent upper airway infections (42%), and epilepsy (21%). Major malformations are less common except for cryptorchidism (46% of males), and cerebral anomalies (70%). Individuals with variants between bp 5,595 and 5,614 of CREBBP show a specific phenotype (ptosis, telecanthi, short and upslanted palpebral fissures, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum). 3D face shape demonstrated resemblance to individuals with a duplication of 16p13.3 (the region that includes CREBBP), possibly indicating a gain of function. The other affected individuals show a less specific phenotype. We conclude that there is now more firm evidence that variants in these specific regions of CREBBP and EP300 result in a phenotype that differs from RSTS, and that this phenotype may be heterogeneous.

Original languageEnglish
Pages (from-to)862-876
Number of pages15
JournalAmerican Journal of Medical Genetics, Part A
Issue number4
Early online date20 Feb 2018
Publication statusPublished - 1 Apr 2018


  • CBP
  • EP300
  • exome sequencing
  • genotype–phenotype correlation
  • intellectual disability


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