Rubinstein-Taybi syndrome due to CREBBP mutations: genes and variants

Genes linked to Rubinstein-Taybi syndrome due to CREBBP mutations

• 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.

  52 disease-causing and 246 uncertain variants in CREBBP are linked to Rubinstein-Taybi syndrome due to CREBBP mutations.

• 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.

  1 disease-causing and 9 uncertain variants in EP300 are linked to Rubinstein-Taybi syndrome due to CREBBP mutations.

Where Rubinstein-Taybi syndrome due to CREBBP mutations variants cluster

• CREBBP CBP/p300-type HAT (positions 1323–1700): 31 of 52 disease-causing changes, 3.9× more than its size predicts.
• CREBBP Interaction with TRERF1 (positions 1460–1891): 20 of 52 disease-causing changes, 2.2× more than its size predicts.
• CREBBP Interaction with ASF1A (positions 1162–1180): 4 of 52 disease-causing changes, 9.9× more than its size predicts.
• CREBBP KIX (positions 587–666): 3 of 52 disease-causing changes, 1.8× more than its size predicts.

Known disease-causing variants in Rubinstein-Taybi syndrome due to CREBBP mutations

Uncertain variants in Rubinstein-Taybi syndrome due to CREBBP mutations that look disease-causing

Which prediction tools work for Rubinstein-Taybi syndrome due to CREBBP mutations

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)
• PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 92 out of 100
• MutPred2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 88 out of 100
• SIFT: 87 out of 100

Same protein, different disease

• Menke-Hennekam syndrome is also caused by CREBBP variants; they fall partly in the same places as the Rubinstein-Taybi syndrome due to CREBBP mutations variants (15 disease-causing).
• Rubinstein-Taybi syndrome is also caused by CREBBP variants; they fall mostly in different places as the Rubinstein-Taybi syndrome due to CREBBP mutations variants (15 disease-causing).
• Rubinstein-Taybi syndrome due to EP300 haploinsufficiency is also caused by EP300 variants; they fall mostly in different places as the Rubinstein-Taybi syndrome due to CREBBP mutations variants (17 disease-causing).
• Menke-Hennekam syndrome is also caused by EP300 variants; they fall mostly in different places as the Rubinstein-Taybi syndrome due to CREBBP mutations variants (4 disease-causing).

Diseases related to Rubinstein-Taybi syndrome due to CREBBP mutations

• Menke-Hennekam syndrome, also linked to CREBBP and EP300
• Rubinstein-Taybi 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 due to CREBBP mutations?

In CATVariant, Rubinstein-Taybi syndrome due to CREBBP mutations 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 due to CREBBP mutations?

400 variants: 53 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 255 are of uncertain significance or have conflicting reports.

Which uncertain variants in Rubinstein-Taybi syndrome due to CREBBP mutations look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CREBBP R1378W. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Rubinstein-Taybi syndrome due to CREBBP mutations?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.92, based on 32 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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