Rare genetic intellectual disability: genes and variants

Genes linked to Rare genetic intellectual disability

• 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.

  1 disease-causing and 0 uncertain variants in CREBBP are linked to Rare genetic intellectual disability.

• DNMT3A: DNA (cytosine-5)-methyltransferase 3A

  It establishes new DNA methylation patterns during development and hematopoietic differentiation. Somatic variants are common in clonal hematopoiesis and acute myeloid leukemia, while germline variants cause Tatton-Brown-Rahman overgrowth syndrome.

  1 disease-causing and 0 uncertain variants in DNMT3A are linked to Rare genetic intellectual disability.

• 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 0 uncertain variants in EP300 are linked to Rare genetic intellectual disability.

Weakly linked (only a few uncertain records): ASH1L and KMT2A.

Known disease-causing variants in Rare genetic intellectual disability

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 Rare genetic intellectual disability variants (52 disease-causing).
• Menke-Hennekam syndrome is also caused by CREBBP variants; they fall mostly in different places as the Rare genetic intellectual disability variants (15 disease-causing).
• Rubinstein-Taybi syndrome is also caused by CREBBP variants; they fall mostly in different places as the Rare genetic intellectual disability variants (15 disease-causing).
• Tatton-Brown-Rahman overgrowth syndrome is also caused by DNMT3A variants; they fall mostly in different places as the Rare genetic intellectual disability variants (32 disease-causing).
• Heyn-Sproul-Jackson syndrome is also caused by DNMT3A variants; they fall mostly in different places as the Rare genetic intellectual disability variants (5 disease-causing).
• Acute myeloid leukemia is also caused by DNMT3A variants; they fall mostly in different places as the Rare genetic intellectual disability variants (5 disease-causing).
• Rubinstein-Taybi syndrome due to EP300 haploinsufficiency is also caused by EP300 variants; they fall mostly in different places as the Rare genetic intellectual disability variants (17 disease-causing).
• Menke-Hennekam syndrome is also caused by EP300 variants; they fall mostly in different places as the Rare genetic intellectual disability variants (4 disease-causing).

Diseases related to Rare genetic intellectual disability

• Rubinstein-Taybi syndrome due to CREBBP mutations, also linked to CREBBP and EP300
• Menke-Hennekam syndrome, also linked to CREBBP and EP300
• Rubinstein-Taybi syndrome, also linked to CREBBP and EP300
• Cone-rod dystrophy, also linked to CREBBP
• Acute myeloid leukemia, also linked to DNMT3A
• Tatton-Brown-Rahman overgrowth syndrome, also linked to DNMT3A
• Colorectal cancer, also linked to EP300
• Rubinstein-Taybi syndrome due to EP300 haploinsufficiency, also linked to EP300
• Carcinoma of colon, also linked to EP300
• Multiple myeloma, also linked to DNMT3A
• Paediatric disorders, also linked to DNMT3A
• Heyn-Sproul-Jackson syndrome, also linked to DNMT3A

Frequently asked questions

Which genes are linked to Rare genetic intellectual disability?

In CATVariant, Rare genetic intellectual disability is linked to 3 analyzed proteins: CREBBP (CREB-binding protein), DNMT3A (DNA (cytosine-5)-methyltransferase 3A) and EP300 (Histone acetyltransferase p300).

How many genetic variants are linked to Rare genetic intellectual disability?

5 variants: 3 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1 are of uncertain significance or have conflicting reports.

Which uncertain variants in Rare genetic intellectual disability look disease-causing?

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

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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