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.

Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein–Taybi and Filippi syndromes

“…The particular 3-bp variant found in our patient has been described once before in a RTS patient, albeit not in mosaic form. 12 This patient's phenotype is similar to ours, with delayed walking, broad thumbs, syndactyly of hands and feet, feeding problems, and retinal coloboma. Unlike the present case, this patient also has a bicuspid aorta valve and typical RTS facial features with a beaked nose and downward slanting palpebral fissures (Dr E Schorry, private communication).…”

Multiplex ligation-dependent probe amplification detection of an unknown large deletion of the CREB-binding protein gene in a patient with Rubinstein-Taybi Syndrome

“…Growth retardation in height and weight has been observed more frequently in patients without CREBBP mutations; seizures were more frequent in those with CREBBP mutations. The degree of ID is similar in all groups, although there is a trend toward lower IQ and autistic features in patients with large deletions (Schorry et al, 2008). These latter features led us to search for large deletions in our patient, although CREBBP gene deletions account only for approximately 10% of RTS patients (Petrij et al, 2000).…”

Congenital Malformations and Syndromes: Early Diagnosis and Prognosis

“…There is genetic heterogeneity and about 25% of patients present with mutations or microdeletions in the gene encoding the transcriptional coactivator CREB-binding protein (16p13.3) [8]. Familial cases with autosomal dominant inheritance have been described.…”