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Case Reports
. 2025 Sep;104(9):4843-4848.
doi: 10.1007/s00277-025-06536-2. Epub 2025 Aug 27.

Rare germline ETV6 variant associated with thrombocytopenia and acute leukemia

Akhil Rajendra Kurup  1   2 , Janet Malcolmson  3   4 , Anita Villani  5 , Raymond H Kim  6   7   8   9   10 , Karen Wl Yee  11   12
Affiliations
Case Reports

Rare germline ETV6 variant associated with thrombocytopenia and acute leukemia

Akhil Rajendra Kurup et al. Ann Hematol. 2025 Sep.

Abstract

Germline mutations in ETV6 have been associated with thrombocytopenia and predisposition to hematological malignancies. Here, we report a pedigree with a multiple family member with an ETV6 c.1127T > A (p.Leu376Gln) variant, initially classified as a variant of uncertain significance (VUS), found to be segregating with thrombocytopenia and hematological/solid tumor malignancies. The proband, a 63-year-old male with chronic thrombocytopenia and a family history of hematological malignancies, presented with pancytopenia and was diagnosed as myelodysplastic syndrome (MDS). Next generation sequencing (NGS) from the bone marrow revealed the ETV6 c.1127T > A (p.Leu376Gln) variant with a variant allele frequency (VAF) of 46%. Germline testing on skin fibroblasts confirmed the presence of the same ETV6 variant in the proband and two of his siblings: one of them was diagnosed with acute lymphoblastic leukemia (ALL) during childhood and therapy-related MDS during adulthood, and another sibling with chronic isolated thrombocytopenia. The ETV6 c.1127T > A (p.Leu376Gln) variant potentially affects the ETS DNA-binding domain, leading to impaired DNA binding with a preserved dimerization capability, resulting in a dominant negative effect by cytoplasmic sequestration. This ETV6 variant has not been reported in a large population database, hence it has been designated as a VUS. Segregation of this variant with thrombocytopenia and hematological/solid tumor malignancies in the pedigree, alongside supporting evidence from other reported ETV6 variants, suggests its pathogenicity. This report highlights the pathogenicity of ETV6 c.1127T > A (p.Leu376Gln) variant and supports its reclassification from VUS to likely pathogenic, adding to the vast evidence of ETV6-associated thrombocytopenia and leukemia predisposition.

Keywords: ETV6; Acute lymphoblastic leukemia; Germline; Myelodysplastic syndrome; Thrombocytopenia.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Ethical review and approval was not required for this case report in accordance with the University Health Network institutional requirements. Written informed consent to participate in this study was provided by the proband’s siblings. Consent for publication: The proband’s siblings provided consent for publication. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Pedigree showing the segregation of the ETV6 c.1127T > A variant within the extended family of the proband
See this image and copyright information in PMC

References

    1. Noetzli L, Lo RW, Lee-Sherick AB et al (2015) Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet 47:535–538 - DOI - PMC - PubMed
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