Myelodysplastic syndrome: genes and variants

Genes linked to Myelodysplastic syndrome

• GATA2: Endothelial transcription factor GATA-2

  It maintains hematopoietic stem and progenitor cells and directs development of monocytes, dendritic cells, NK cells, and other blood lineages. Haploinsufficiency causes GATA2 deficiency with immunodeficiency, cytopenias, and high risk of myelodysplastic syndrome or AML.

  2 disease-causing and 9 uncertain variants in GATA2 are linked to Myelodysplastic syndrome.

• SF3B1: Splicing factor 3B subunit 1

  It recognizes branch-point regions during spliceosome assembly and helps define correct 3-prime splice sites. Recurrent hotspot mutations alter splice-site choice and drive myelodysplastic syndromes, chronic lymphocytic leukemia, uveal melanoma, and other cancers.

  2 disease-causing and 3 uncertain variants in SF3B1 are linked to Myelodysplastic syndrome.

• ASXL1: Polycomb group protein ASXL1

  It regulates developmental and hematopoietic transcription through interactions with Polycomb and other chromatin-modifying systems. Somatic truncating variants are common in clonal hematopoiesis and myeloid malignancies, while germline pathogenic variants cause Bohring-Opitz syndrome.

  0 disease-causing and 4 uncertain variants in ASXL1 are linked to Myelodysplastic syndrome.

• TET2: Methylcytosine dioxygenase TET2

  It oxidizes methylated cytosines and helps reshape DNA methylation during hematopoietic differentiation. Somatic loss-of-function variants are among the most common drivers of clonal hematopoiesis and occur frequently in myeloid malignancies.

  0 disease-causing and 2 uncertain variants in TET2 are linked to Myelodysplastic syndrome.

• BCR: Breakpoint cluster region protein

  It has serine/threonine kinase and GTPase-regulatory functions involved in cytoskeletal and signaling control. Chromosomal fusion with ABL1 creates the constitutively active BCR::ABL1 kinase that drives chronic myeloid leukemia and subsets of acute leukemia.

  0 disease-causing and 0 uncertain variants in BCR are linked to Myelodysplastic syndrome.

• CRBN: Protein cereblon

  It determines substrate recognition for the CRL4-CRBN ubiquitin ligase and thereby controls degradation of selected cellular proteins. Thalidomide and related drugs bind CRBN and redirect the ligase toward new substrates, a mechanism central to their therapeutic and teratogenic effects.

  0 disease-causing and 0 uncertain variants in CRBN are linked to Myelodysplastic syndrome.

• CSF3R: Granulocyte colony-stimulating factor receptor

  It transmits G-CSF signals that promote neutrophil precursor proliferation, differentiation, and survival. Activating or truncating somatic variants are major drivers of chronic neutrophilic leukemia, while loss-of-function variants can cause severe congenital neutropenia.

  0 disease-causing and 0 uncertain variants in CSF3R are linked to Myelodysplastic syndrome.

• CUX1: Homeobox protein cut-like 1

  It regulates transcription and chromatin-associated processes involved in cell differentiation, proliferation, and neuronal development. Haploinsufficiency can cause neurodevelopmental impairment, while somatic loss is common in myeloid malignancies and often marks adverse-risk disease.

  0 disease-causing and 0 uncertain variants in CUX1 are linked to Myelodysplastic syndrome.

• DDX41: Probable ATP-dependent RNA helicase DDX41

  It participates in RNA processing, ribosome biology, and innate nucleic-acid sensing in hematopoietic cells. Germline loss-of-function variants strongly predispose to myelodysplastic syndrome and acute myeloid leukemia, often after acquisition of a second somatic DDX41 variant.

  0 disease-causing and 0 uncertain variants in DDX41 are linked to Myelodysplastic syndrome.

• DNMT1: DNA (cytosine-5)-methyltransferase 1

  It copies existing DNA methylation patterns during replication and also contributes to chromatin regulation and neuronal maintenance. Dominant pathogenic variants can cause hereditary sensory neuropathy with dementia and hearing loss or a cerebellar ataxia-deafness-narcolepsy syndrome.

  0 disease-causing and 0 uncertain variants in DNMT1 are linked to Myelodysplastic 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.

  0 disease-causing and 0 uncertain variants in DNMT3A are linked to Myelodysplastic syndrome.

• FANCC: Fanconi anemia group C protein

  It contributes to activation of the FANCD2-FANCI DNA-repair pathway after replication-blocking lesions. Biallelic loss-of-function variants cause Fanconi anemia group C, with chromosome instability, marrow failure, congenital abnormalities, and elevated cancer risk.

  0 disease-causing and 0 uncertain variants in FANCC are linked to Myelodysplastic syndrome.

• POLD1: DNA polymerase delta catalytic subunit

  It performs much of lagging-strand DNA synthesis and proofreads newly replicated DNA through its exonuclease activity. Germline proofreading-domain variants cause polymerase-proofreading-associated polyposis and cancer predisposition, while other variants can produce developmental progeroid syndromes.

  0 disease-causing and 0 uncertain variants in POLD1 are linked to Myelodysplastic syndrome.

• POLE: DNA polymerase epsilon catalytic subunit A

  It performs leading-strand DNA synthesis and proofreads newly incorporated bases during replication. Germline exonuclease-domain variants cause polymerase-proofreading-associated polyposis, while somatic proofreading defects create ultramutated tumors with distinctive mutation signatures.

  0 disease-causing and 0 uncertain variants in POLE are linked to Myelodysplastic syndrome.

• SETBP1: SET-binding protein

  It regulates transcription and protein-phosphatase signaling in development and hematopoiesis. Specific gain-of-function variants cause Schinzel-Giedion syndrome, somatic hotspot variants occur in aggressive myeloid neoplasms, and loss-of-function variants can cause a distinct speech and developmental disorder.

  0 disease-causing and 0 uncertain variants in SETBP1 are linked to Myelodysplastic syndrome.

• SRSF2: Serine/arginine-rich splicing factor 2

  It helps select splice sites during pre-mRNA processing and coordinates multiple stages of RNA maturation. Recurrent P95 hotspot mutations change RNA-binding preferences and are common in myelodysplastic syndromes, chronic myelomonocytic leukemia, and AML.

  0 disease-causing and 0 uncertain variants in SRSF2 are linked to Myelodysplastic syndrome.

• TERT: Telomerase reverse transcriptase

  It extends telomeric DNA using an internal RNA template and helps counter progressive chromosome-end shortening in stem and proliferative cells. Loss-of-function variants cause telomere-biology disorders, while promoter activation and increased activity support unlimited proliferation in many cancers.

  0 disease-causing and 0 uncertain variants in TERT are linked to Myelodysplastic syndrome.

• TGFB2: Transforming growth factor beta-2 proprotein

  Its secreted signaling regulates extracellular matrix, cell differentiation, proliferation, and cardiovascular development. Haploinsufficiency causes a Loeys-Dietz-spectrum connective-tissue disorder with increased risk of thoracic aortic aneurysm and dissection.

  0 disease-causing and 0 uncertain variants in TGFB2 are linked to Myelodysplastic syndrome.

Weakly linked (only a few uncertain records): ERBB2.

Known disease-causing variants in Myelodysplastic syndrome

Same protein, different disease

• Deafness-lymphedema-leukemia syndrome is also caused by GATA2 variants; they fall mostly in different places as the Myelodysplastic syndrome variants (35 disease-causing).
• GATA2 deficiency with susceptibility to MDS/AML is also caused by GATA2 variants; they fall mostly in different places as the Myelodysplastic syndrome variants (32 disease-causing).
• Monocytopenia with susceptibility to infections is also caused by GATA2 variants; they fall mostly in different places as the Myelodysplastic syndrome variants (12 disease-causing).

Diseases related to Myelodysplastic syndrome

• Acute myeloid leukemia, also linked to ASXL1, CSF3R, DDX41, DNMT1 and 9 more
• Ovarian cancer, also linked to FANCC, POLD1 and POLE
• Colorectal cancer, also linked to POLD1 and POLE
• Non-small cell lung carcinoma, also linked to POLD1 and POLE
• Multiple myeloma, also linked to CRBN and DNMT3A
• Familial colorectal cancer, also linked to POLD1 and POLE
• Ebv-positive nodal t- and nk-cell lymphoma, also linked to DNMT3A and TET2
• Familial thoracic aortic aneurysm and aortic dissection, also linked to TGFB2
• Ehlers-Danlos syndrome, also linked to TGFB2
• Gastrointestinal stromal tumor, also linked to BCR
• Loeys-Dietz syndrome, also linked to TGFB2
• Autosomal dominant nonsyndromic hearing loss, also linked to POLE

Frequently asked questions

Which genes are linked to Myelodysplastic syndrome?

In CATVariant, Myelodysplastic syndrome is linked to 18 analyzed proteins: GATA2 (Endothelial transcription factor GATA-2), SF3B1 (Splicing factor 3B subunit 1), ASXL1 (Polycomb group protein ASXL1), TET2 (Methylcytosine dioxygenase TET2), BCR (Breakpoint cluster region protein), CRBN (Protein cereblon) and 12 more.

How many genetic variants are linked to Myelodysplastic syndrome?

30 variants: 4 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 18 are of uncertain significance or have conflicting reports.

Which uncertain variants in Myelodysplastic syndrome 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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