Tatton-Brown-Rahman overgrowth syndrome: genes and variants

Genes linked to Tatton-Brown-Rahman overgrowth syndrome

• 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.

  32 disease-causing and 176 uncertain variants in DNMT3A are linked to Tatton-Brown-Rahman overgrowth syndrome.

Where Tatton-Brown-Rahman overgrowth syndrome variants cluster

• DNMT3A SAM-dependent MTase C5-type (positions 634–912): 19 of 32 disease-causing changes, 1.9× more than its size predicts.
• DNMT3A PHD-type (positions 534–590): 6 of 32 disease-causing changes, 3.0× more than its size predicts.

Known disease-causing variants in Tatton-Brown-Rahman overgrowth syndrome

Uncertain variants in Tatton-Brown-Rahman overgrowth syndrome that look disease-causing

Which prediction tools work for Tatton-Brown-Rahman overgrowth syndrome

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

• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 95 out of 100
• SIFT: 94 out of 100
• phyloP: 91 out of 100

Same protein, different disease

• Heyn-Sproul-Jackson syndrome is also caused by DNMT3A variants; they fall partly in the same places as the Tatton-Brown-Rahman overgrowth syndrome variants (5 disease-causing).

Diseases related to Tatton-Brown-Rahman overgrowth syndrome

• Acute myeloid leukemia, also linked to DNMT3A
• Multiple myeloma, also linked to DNMT3A
• Paediatric disorders, also linked to DNMT3A
• Heyn-Sproul-Jackson syndrome, also linked to DNMT3A
• Myelodysplastic syndrome, also linked to DNMT3A
• Rare genetic intellectual disability, also linked to DNMT3A
• Ebv-positive nodal t- and nk-cell lymphoma, also linked to DNMT3A

Frequently asked questions

Which genes are linked to Tatton-Brown-Rahman overgrowth syndrome?

In CATVariant, Tatton-Brown-Rahman overgrowth syndrome is linked to 1 analyzed protein: DNMT3A (DNA (cytosine-5)-methyltransferase 3A).

How many genetic variants are linked to Tatton-Brown-Rahman overgrowth syndrome?

252 variants: 32 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 176 are of uncertain significance or have conflicting reports.

Which uncertain variants in Tatton-Brown-Rahman overgrowth syndrome look disease-causing?

4 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example DNMT3A R749S, DNMT3A C586Y, DNMT3A R736C and DNMT3A R882S. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Tatton-Brown-Rahman overgrowth syndrome?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 28 disease-causing and 10 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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