Rubinstein–Taybi syndrome

The estimated prevalence is 1/100,000 to 1/125,000 (Hennekam et al., 1990).

Rubinstein-Taybi syndrome is inherited in an autosomal dominant manner. Most affected individuals represent simplex cases caused by a de novo pathogenic variant; recurrence risk for unaffected parents is low but not negligible because of the possibility of parental somatic or germline mosaicism. The recurrence risk for offspring of an affected individual is 50%. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of Rubinstein-Taybi syndrome is established in a proband with characteristic clinical features and identification of a heterozygous germline pathogenic variant in CREBBP or EP300 by molecular genetic testing. Brain MRI commonly demonstrates a dysmorphic or dysplastic corpus callosum in approximately 74% of affected individuals; this finding is supportive but not diagnostic.

Main differential diagnoses include:

• Floating-Harbor syndrome: overlapping facial features (low-hanging columella), short stature, and short thumbs with broad fingertips, but normal head circumference and absence of downslanting palpebral fissures, with thumbs not deviated and halluces not broad; SRCAP.
• : short stature, facial dysmorphism, and intellectual disability with limb reduction defects, distinguishing it from the broad-thumb phenotype of Rubinstein-Taybi syndrome; NIPBL, SMC1A, SMC3, RAD21, HDAC8, BRD4.
• Wiedemann-Steiner syndrome: short stature, facial dysmorphism, and intellectual disability with hypertrichosis cubiti and absence of the typical broad and angulated thumb and hallux findings; KMT2A.

• Establishing the molecular diagnosis confirms the clinical suspicion, ends the diagnostic odyssey, and informs prognosis.
• Identification of the causative variant enables specific and individualised surveillance and clinical management of known complications across cardiac, ophthalmologic, audiologic, dental, orthopaedic, neurologic, and dermatologic systems, and is a prerequisite for targeted medical care; decisions on implementation lie with the treating physicians in consultation with the affected individual.
• Knowledge of the familial pathogenic variant enables predictive and carrier testing of at-risk relatives within the framework of genetic counselling.

• Rubinstein-Taybi Syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Updated 9 November 2023. Available from: (GeneReviews, NBK1526; accessed June 2026).
• Hennekam RC, Van Den Boogaard MJ, Sibbles BJ, Van Spijker HG. Rubinstein-Taybi syndrome in The Netherlands. American Journal of Medical Genetics. Supplement. 1990;6:17-29. doi: 10.1002/ajmg.1320370604. PMID: .
• Fergelot P, Van Belzen M, Van Gils J, Afenjar A, Armour CM, Arveiler B, et al. Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations. American Journal of Medical Genetics. Part A. 2016;170(12):3069-3082. doi: 10.1002/ajmg.a.37940. PMID: .
• Cohen JL, Schrier Vergano SA, Mazzola S, Strong A, Keena B, McDougall C, et al. EP300-related Rubinstein-Taybi syndrome: Highlighted rare phenotypic findings and a genotype-phenotype meta-analysis of 74 patients. American Journal of Medical Genetics. Part A. 2020;182(12):2926-2938. doi: 10.1002/ajmg.a.61883. PMID: .