Molecular phenotype and bleeding risks of an inherited platelet disorder in a family with a RUNX1 frameshift mutation

Haemophilia. 2017 May;23(3):e204-e213. doi: 10.1111/hae.13169. Epub 2017 Feb 8.


Introduction: Inherited defects in RUNX1 are important causes of platelet function disorders.

Aim: Our goals were to evaluate RUNX1-related platelet disorders among individuals evaluated for uncharacterized, inherited platelet function disorders and test a proof of concept that bleeding risks could be quantitatively estimated for typical families with an inherited platelet function disorder.

Methods: Index cases with an uncharacterized inherited platelet function disorder were subjected to exome sequencing with confirmation of RUNX1 mutations by Sanger sequencing. Laboratory findings were obtained from medical records and persistence of platelet non-muscle myosin heavy chain IIB (MYH10), a biomarker of RUNX1 defects, was assessed by Western blotting. Bleeding histories were assessed using standardized assessment tools. Bleeding risks were estimated as odds ratios (OR) using questionnaire data for affected individuals compared to controls.

Results: Among 12 index cases who had their exomes sequenced, one individual from a family with eight study participants had a c.583dup in RUNX1 that segregated with the disease and was predicted to cause a frameshift and RUNX1 haploinsufficiency. Unlike unaffected family members (n = 2), affected family members (n = 6) had increased bleeding scores and abnormal platelet aggregation and dense granule release responses to agonists but only some had thrombocytopenia and/or dense granule deficiency. This family's mutation was associated with persistence of MYH10 in platelets and increased risks (OR 11-440) for wound healing problems and mild bleeding symptoms, including bleeding interfering with lifestyle in women.

Conclusion: Inherited platelet dysfunction due to a RUNX1 haploinsufficiency mutation significantly increases bleeding risks.

Keywords: RUNX1 mutation; bleeding risks; blood platelet disorders; exome sequencing; wound healing.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Base Sequence
  • Blood Platelet Disorders / complications*
  • Blood Platelet Disorders / genetics*
  • Child
  • Child, Preschool
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Female
  • Frameshift Mutation*
  • Hemorrhage / complications*
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype*
  • Risk
  • Young Adult


  • Core Binding Factor Alpha 2 Subunit