CREBBP variants were first reported in relation to autosomal dominant Rubinstein-Taybi syndrome in 1995 (PMID: 7630403). CREBBP encodes cAMP-response element binding protein, or CBP, involved in coupling chromatin remodeling to transcription factor recognition crucial for embryonic development, growth, and homeostasis. Rubinstein-Taybi syndrome is characterized by broad digits, microcephaly, distinctive facial dysmorphisms, intellectual disability, and seizures.
Eight unique variants (nonsense, frameshift, missense, splice site, deletion) have been reported in eight probands in four publications (PMIDs: 18792986, 12566391, 11331617, 12070251) included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached.
This gene-disease relationship is also supported by an animal rescue studying memory enhancement, a CBP-deficient mouse model, biochemical function, and CBP acetyltransferase enzymatic activity experimental evidence (PMIDs: 12930888, 9294190, 11331617, 12566391).
In summary, CREBBP is definitively associated with autosomal dominant Rubinstein-Taybi syndrome. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on April 27, 2018. As of June 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
CREBBP was first reported in relation to autosomal dominant Rubinstein-Taybi syndrome in 1995 (Petrij et al., PMID: 7630403). CREBBP encodes a transcriptional coactivator with histone acetyltransferase activity. Rubinstein-Taybi syndrome is characterized by intellectual disability, distinctive facial dysmorphisms, broad digits, short stature, and microcephaly.
Eight variants (nonsense, frameshift, missense, splice site, and deletion) that have been reported in eight probands in four publications (PMIDs: 11331617, 12070251, 12566391, 18792986) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including a Crebbp-deficient mouse model, a rescue experiment, and biochemical function (PMIDs: 9294190, 11331617, 12566391, 12930888).
In summary, there is definitive evidence supporting the relationship between CREBBP and autosomal dominant Rubinstein-Taybi syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 27, 2018 (SOP Version 5). As of June 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
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