CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype.
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. © 2016 Wiley Periodicals, Inc.
Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.
Leonie A
LA
Menke
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Martine J
MJ
van Belzen
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Marielle
M
Alders
Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
Francesca
F
Cristofoli
Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Nadja
N
Ehmke
Department of Genetics, and INSERM U1211, University Hospital of Bordeaux, Bordeaux, France.
Patricia
P
Fergelot
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.|Clinical Genetics Unit, University of Birmingham, Birmingham, United Kingdom.
Alison
A
Foster
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Erica H
EH
Gerkes
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Mariëtte J V
MJ
Hoffer
Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Denise
D
Horn
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Sarina G
SG
Kant
Department of Genetics, and INSERM U1211, University Hospital of Bordeaux, Bordeaux, France.
Didier
D
Lacombe
Division of Genetics and Metabolism, Children's National Health System, Washington, District of Columbia.
Eyby
E
Leon
Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.|Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Saskia M
SM
Maas
Department of Translational Medical Science, Federico II University, Naples, Italy.
Daniela
D
Melis
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Valentina
V
Muto
Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, United Kingdom.
Soo-Mi
SM
Park
Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
Hilde
H
Peeters
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Dorien J M
DJ
Peters
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Rolph
R
Pfundt
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Conny M A
CM
van Ravenswaaij-Arts
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Marco
M
Tartaglia
Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands. r.c.hennekam@amc.uva.nl.
Raoul C M
RC
Hennekam
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D050882:CREB-Binding Protein / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005091:Exons; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D012415:Rubinstein-Taybi Syndrome / Q000175:diagnosis* / Q000235:genetics*; D055815:Young Adult
D050882:CREB-Binding Protein
CREBBP; RSTS; Rubinstein-Taybi syndrome; case series; clinical features; exon 30; exon 31; genotype-phenotype correlation; intellectual disability; mutation; syndrome; whole exome sequencing