CREBBP – Rubinstein-Taybi syndrome

Rubinstein-Taybi syndrome (RTS; MONDO:0019188) is a rare autosomal dominant disorder characterized by broad thumbs, facial dysmorphism, postnatal growth delay, and intellectual disability ([HP:0001249], [HP:0001510])1. Heterozygous variants in CREBBP (HGNC:2348) underlie 50–70% of RTS cases, with most arising de novo2.

The inheritance is autosomal dominant with de novo occurrence in >95% of cases. Sequencing across cohorts totaling 395 unrelated probands revealed truncating (frameshift, nonsense), splice-site, and missense variants concentrated in the histone acetyltransferase (HAT) domain ([PMID:32827181])3. A recurrent de novo nonsense variant, c.1066C>T (p.Gln356Ter), has been documented in a 6.5-year-old girl with classic RTS features ([PMID:26603346])4. Maternal germline mosaicism was demonstrated in two affected siblings carrying c.4361T>A (p.Leu1454His), confirming segregation and recurrence risk ([PMID:23352794])5.

Variant spectrum analysis of 164 CREBBP mutations identified 25% frameshift, 23% gross deletions, and 18% nonsense variants without clear hot-spot clustering ([PMID:37017262])6. These findings expand the molecular spectrum and highlight the predominance of loss-of-function alleles in RTS pathogenesis.

Functional studies show that PHD finger mutations such as p.Glu1278Lys abolish HAT activity, reducing histone acetylation by ∼50% in patient lymphoblastoid cells ([PMID:12566391])7. Similarly, truncating CREBBP variants lead to significant deficits in histone H2A/H2B acetylation, reversible by HDAC inhibition ([PMID:21984751])8, supporting haploinsufficiency as the disease mechanism.

Allelic heterogeneity is evidenced by C-terminal missense variants causing distinct Menke-Hennekam phenotypes and non-classical presentations, which warrant careful phenotypic assessment ([PMID:27311832], [PMID:38927590])9,10. Nevertheless, truncating and large-deletion variants consistently associate with the classical RTS phenotype.

Overall, the clinical, genetic, and functional evidence establishes a definitive association between CREBBP and RTS. CREBBP haploinsufficiency due to de novo loss-of-function variants underpins RTS, guiding diagnostic sequencing, recurrence risk counseling, and potential epigenetic therapies. Key take-home: screening for CREBBP variants is essential for accurate RTS diagnosis and management.

References

• Rubinstein-Taybi syndrome and CREBBP c.201 202delTA mutation: a case presenting with varicella meningoencephalitis. Genetic counseling (Geneva, Switzerland) | 2009 [PMID:19852432]
• CREBBP and EP300 mutational spectrum and clinical presentations in a cohort of Swedish patients with Rubinstein-Taybi syndrome. Molecular genetics & genomic medicine | 2016 [PMID:32827181]
• Identification of a novel de novo mutation of CREBBP in a patient with Rubinstein-Taybi syndrome by targeted next-generation sequencing: a case report. Human pathology | 2016 [PMID:26603346]
• Germline mosaicism in Rubinstein-Taybi syndrome. Gene | 2013 [PMID:23352794]
• Genotype-phenotype analysis of ocular findings in Rubinstein-Taybi syndrome - A case report and review of literature. Ophthalmic genetics | 2024 [PMID:37017262]
• Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome. Human molecular genetics | 2003 [PMID:12566391]
• Histone acetylation deficits in lymphoblastoid cell lines from patients with Rubinstein-Taybi syndrome. Journal of medical genetics | 2012 [PMID:21984751]
• CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype. American journal of medical genetics. Part A | 2016 [PMID:27311832]
• The Phenotype-Based Approach Can Solve Cold Cases: The Paradigm of Mosaic Mutations of the CREBBP Gene. Genes | 2024 [PMID:38927590]

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