Novel phenotypes observed in patients with ETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelic ARID5B risk allele as leukaemogenic cofactor

J Med Genet. 2020 Jun;57(6):427-433. doi: 10.1136/jmedgenet-2019-106339. Epub 2019 Nov 8.


Background. The phenotypes of patients with the recently discovered, dominant, ETV6-linked leukaemia predisposition and familial thrombocytopenia syndrome are variable, and the exact mechanism of leukaemogenesis remains unclear. Patients and Methods. Here, we present novel clinical and laboratory phenotypes of seven individuals from three families with ETV6 germline mutations and a refined genetic analysis of one child with additional high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL), aiming to elucidate second oncogenic hits. Results. Four individuals from two pedigrees harboured one novel or one previously described variant in the central domain of ETV6 (c.592C>T, p.Gln198* or c.641C>T, p.Pro241Leu, respectively). Neutropenia was an accompanying feature in one of these families that also harboured a variant in RUNX1 (c.1098_1103dup, p.Ile366_Gly367dup), while in the other, an autism-spectrum disorder was observed. In the third family, the index patient suffered from HD-ALL and life-threatening pulmonary mucor mycosis, and had a positive family history of 'immune' thrombocytopenia. Genetic analyses revealed a novel heterozygous mutation in the ETS domain of ETV6 (c.1136T>C, p.Leu379Pro) along with absence of heterozygosity of chromosome (10)(q21.2q21.3), yielding a biallelic leukaemia risk allele in ARID5B (rs7090445-C). The neutrophil function was normal in all individuals tested, and the platelet immune histochemistry of all three pedigrees showed delta-storage-pool defect-like features and cytoskeletal defects. Conclusions. Our clinical observations and results of high-resolution genetic analyses extend the spectrum of possible phenotypes cosegregating with ETV6 germline mutations. Further, we propose ARID5B as potential leukaemogenic cofactor in patients with ETV6-linked leukaemia predisposition and familial thrombocytopenia syndrome.

Keywords: Immune thrombocytopenia (ITP); cancer predisposition syndrome (CPS); delta-storage pool defect, congenital thrombocytopenia / thrombocytopathy syndrome; genetic susceptibility to leukemia; high-hyperdiploid acute lymphoblastic leukemia (HD-ALL).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Child
  • Child, Preschool
  • Core Binding Factor Alpha 2 Subunit / genetics
  • DNA-Binding Proteins / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Germ-Line Mutation / genetics
  • Heterozygote
  • Humans
  • Infant
  • Leukemia / complications
  • Leukemia / genetics*
  • Leukemia / pathology
  • Male
  • Pedigree
  • Phenotype
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / complications
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Proto-Oncogene Proteins c-ets / genetics*
  • Repressor Proteins / genetics*
  • Thrombocytopenia / complications
  • Thrombocytopenia / genetics*
  • Thrombocytopenia / pathology
  • Transcription Factors / genetics*
  • Young Adult


  • ARID5B protein, human
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • ETS translocation variant 6 protein
  • Proto-Oncogene Proteins c-ets
  • RUNX1 protein, human
  • Repressor Proteins
  • Transcription Factors