title: Genotype-phenotype correlations in Rubinstein-Taybi syndrome.
abstract: Rubinstein-Taybi syndrome (RTS) is a rare multiple congenital anomaly/intellectual impairment syndrome. Loss of function in CREBBP or EP300 genes has been found in about 50% of patients with RTS. Genotype-phenotype correlations were investigated in 93 patients meeting diagnostic criteria for RTS during 2 international RTS family conferences. Mutation analysis of CREBBP was performed on all 31 coding exons and exon-intron junctions; a subset of patients had FISH analysis for large deletions. A total of 64 different variations were observed in the DNA sequence, and determined to be definitive mutations in 52 patients (56%). Mutations detected included: 10 missense mutations; 36 truncating or splice-site mutations; and 6 large deletions detectable by FISH. Fourteen patients had synonymous changes of unknown significance. The majority of mutations affected the HAT domain of CREBBP or predicted termination of the protein before the HAT region. Extensive phenotypic data were collected on each patient and analyzed to determine correlations with mutation types, that is, truncating, large deletions, single amino acid substitutions, or no CREBBP mutation. All four groups displayed the characteristic facial and thumb dysmorphology. Growth retardation in height and weight was seen more frequently in patients with no CREBBP mutation; seizure disorder was more frequent in those with CREBBP mutations. Degree of mental retardation was similar in all groups, although there was a trend toward lower IQ and autistic features in patients with large deletions. Similarity in phenotype between the groups implies that the several genes involved in causing RTS likely have effects through the same pathway.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. elizabeth.schorry@cchmc.org
authors.forename: E K
authors.initials: EK
authors.lastname: Schorry
authors.forename: M
authors.initials: M
authors.lastname: Keddache
authors.forename: N
authors.initials: N
authors.lastname: Lanphear
authors.forename: J H
authors.initials: JH
authors.lastname: Rubinstein
authors.forename: S
authors.initials: S
authors.lastname: Srodulski
authors.forename: D
authors.initials: D
authors.lastname: Fletcher
authors.forename: R I
authors.initials: RI
authors.lastname: Blough-Pfau
authors.forename: G A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D019943:Amino Acid Substitution; D001321:Autistic Disorder / Q000235:genetics; D050882:CREB-Binding Protein / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D005091:Exons; D017353:Gene Deletion; D005838:Genotype; D006130:Growth Disorders / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D012189:Retrospective Studies; D012415:Rubinstein-Taybi Syndrome / Q000175:diagnosis / Q000235:genetics*
chemical_list: D050882:CREB-Binding Protein