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Am J Med Genet A. 2016 Oct;170(10):2681-93. doi: 10.1002/ajmg.a.37800. Epub 2016 Jun 17.

CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype.

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Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Department of Genetics, and INSERM U1211, University Hospital of Bordeaux, Bordeaux, France.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Clinical Genetics Unit, University of Birmingham, Birmingham, United Kingdom.
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Division of Genetics and Metabolism, Children's National Health System, Washington, District of Columbia.
Department of Translational Medical Science, Federico II University, Naples, Italy.
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, United Kingdom.
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.


Mutations in CREBBP cause Rubinstein-Taybi syndrome. By using exome sequencing, and by using Sanger in one patient, CREBBP mutations were detected in 11 patients who did not, or only in a very limited manner, resemble Rubinstein-Taybi syndrome. The combined facial signs typical for Rubinstein-Taybi syndrome were absent, none had broad thumbs, and three had only somewhat broad halluces. All had apparent developmental delay (being the reason for molecular analysis); five had short stature and seven had microcephaly. The facial characteristics were variable; main characteristics were short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum. Six patients had autistic behavior, and two had self-injurious behavior. Other symptoms were recurrent upper airway infections (n = 5), feeding problems (n = 7) and impaired hearing (n = 7). Major malformations occurred infrequently. All patients had a de novo missense mutation in the last part of exon 30 or beginning of exon 31 of CREBBP, between base pairs 5,128 and 5,614 (codons 1,710 and 1,872). No missense or truncating mutations in this region have been described to be associated with the classical Rubinstein-Taybi syndrome phenotype. No functional studies have (yet) been performed, but we hypothesize that the mutations disturb protein-protein interactions by altering zinc finger function. We conclude that patients with missense mutations in this specific CREBBP region show a phenotype that differs substantially from that in patients with Rubinstein-Taybi syndrome, and may prove to constitute one (or more) separate entities.


CREBBP; RSTS; Rubinstein-Taybi syndrome; case series; clinical features; exon 30; exon 31; genotype-phenotype correlation; intellectual disability; mutation; syndrome; whole exome sequencing

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