Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy

Michael Y. Zhang, Jane E. Churpek, Siobán B. Keel, Tom Walsh, Ming K. Lee, Keith R. Loeb, Suleyman Gulsuner, Colin C. Pritchard, Marilyn Sanchez-Bonilla, Jeffrey J. Delrow, Ryan S. Basom, Melissa Forouhar, Boglarka Gyurkocza, Bradford S. Schwartz, Barbara Neistadt, Rafael Marquez, Christopher J. Mariani, Scott A. Coats, Inga Hofmann, R. Coleman LindsleyDavid A. Williams, Janis L. Abkowitz, Marshall S. Horwitz, Mary Claire King, Lucy A. Godley, Akiko Shimamura*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

286 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)180-185
Number of pages6
JournalNature Genetics
Issue number2
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Genetics


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