Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy

Nat Genet. 2015 Feb;47(2):180-5. doi: 10.1038/ng.3177. Epub 2015 Jan 12.


We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation
  • Exons / genetics
  • Female
  • Genes, Reporter
  • Germ-Line Mutation
  • HeLa Cells
  • Hematologic Neoplasms / genetics*
  • Humans
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense
  • Pedigree
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-ets / genetics*
  • Recombinant Proteins
  • Repressor Proteins / genetics*
  • Sequence Analysis, RNA
  • Thrombocytopenia / genetics*


  • ETS translocation variant 6 protein
  • Proto-Oncogene Proteins c-ets
  • Recombinant Proteins
  • Repressor Proteins

Associated data

  • GDB/SCV000195553
  • GDB/SCV000195554
  • GDB/SCV000195555
  • SRA/SRP048957