Rubinstein-Taybi syndrome: genes and variants

Genes linked to Rubinstein-Taybi syndrome

• CREBBP: CREB-binding protein

  It acetylates histones and integrates signals from many transcription factors to regulate developmental and activity-dependent gene expression. Germline loss-of-function variants cause Rubinstein-Taybi syndrome, while somatic alterations occur in several cancers.

  15 disease-causing and 448 uncertain variants in CREBBP are linked to Rubinstein-Taybi syndrome.

• EP300: Histone acetyltransferase p300

  It acetylates histones and transcription factors and acts as a central coactivator for developmental and stress-responsive transcription. Germline loss-of-function variants cause Rubinstein-Taybi syndrome type 2, while acquired alterations occur in several cancers.

  0 disease-causing and 2 uncertain variants in EP300 are linked to Rubinstein-Taybi syndrome.

Where Rubinstein-Taybi syndrome variants cluster

• CREBBP Interaction with TRERF1 (positions 1460–1891): 10 of 15 disease-causing changes, 3.8× more than its size predicts.
• CREBBP CBP/p300-type HAT (positions 1323–1700): 8 of 15 disease-causing changes, 3.5× more than its size predicts.

Known disease-causing variants in Rubinstein-Taybi syndrome

Which prediction tools work for Rubinstein-Taybi syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 94 out of 100
• EVE: 91 out of 100
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 87 out of 100
• MutPred2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Rubinstein-Taybi syndrome due to CREBBP mutations is also caused by CREBBP variants; they fall mostly in different places as the Rubinstein-Taybi syndrome variants (52 disease-causing).
• Menke-Hennekam syndrome is also caused by CREBBP variants; they fall mostly in different places as the Rubinstein-Taybi syndrome variants (15 disease-causing).

Diseases related to Rubinstein-Taybi syndrome

• Rubinstein-Taybi syndrome due to CREBBP mutations, also linked to CREBBP and EP300
• Menke-Hennekam syndrome, also linked to CREBBP and EP300
• Rare genetic intellectual disability, also linked to CREBBP and EP300
• Cone-rod dystrophy, also linked to CREBBP
• Colorectal cancer, also linked to EP300
• Rubinstein-Taybi syndrome due to EP300 haploinsufficiency, also linked to EP300
• Carcinoma of colon, also linked to EP300

Frequently asked questions

Which genes are linked to Rubinstein-Taybi syndrome?

In CATVariant, Rubinstein-Taybi syndrome is linked to 2 analyzed proteins: CREBBP (CREB-binding protein) and EP300 (Histone acetyltransferase p300).

How many genetic variants are linked to Rubinstein-Taybi syndrome?

656 variants: 15 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 450 are of uncertain significance or have conflicting reports.

Which uncertain variants in Rubinstein-Taybi syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Rubinstein-Taybi syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 9 disease-causing and 22 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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