M S Badin1, J K Iyer1, M Chong1, L Graf1, G E Rivard2, J S Waye1, A D Paterson3,4, G Pare5, C P M Hayward6. 1. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. 2. Hematology/Oncology, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada. 3. Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada. 4. The Dalla Lana School of Public Health and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. 5. Hamilton Regional Laboratory Medicine Program, Hamilton, ON, Canada. 6. Department of Medicine, McMaster University, Hamilton, ON, Canada.
Abstract
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.
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 RUNX1haploinsufficiency. 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 RUNX1haploinsufficiency mutation significantly increases bleeding risks.
Authors: Justin Brunet; Matthew Badin; Michael Chong; Janaki Iyer; Subia Tasneem; Lucas Graf; Georges E Rivard; Andrew D Paterson; Guillaume Pare; Catherine P M Hayward Journal: Res Pract Thromb Haemost Date: 2020-05-30
Authors: Anna L Brown; Peer Arts; Catherine L Carmichael; Milena Babic; Julia Dobbins; Chan-Eng Chong; Andreas W Schreiber; Jinghua Feng; Kerry Phillips; Paul P S Wang; Thuong Ha; Claire C Homan; Sarah L King-Smith; Lesley Rawlings; Cassandra Vakulin; Andrew Dubowsky; Jessica Burdett; Sarah Moore; Grace McKavanagh; Denae Henry; Amanda Wells; Belinda Mercorella; Mario Nicola; Jeffrey Suttle; Ella Wilkins; Xiao-Chun Li; Joelle Michaud; Peter Brautigan; Ping Cannon; Meryl Altree; Louise Jaensch; Miriam Fine; Carolyn Butcher; Richard J D'Andrea; Ian D Lewis; Devendra K Hiwase; Elli Papaemmanuil; Marshall S Horwitz; Georges Natsoulis; Hugh Y Rienhoff; Nigel Patton; Sally Mapp; Rachel Susman; Susan Morgan; Julian Cooney; Mark Currie; Uday Popat; Tilmann Bochtler; Shai Izraeli; Kenneth Bradstock; Lucy A Godley; Alwin Krämer; Stefan Fröhling; Andrew H Wei; Cecily Forsyth; Helen Mar Fan; Nicola K Poplawski; Christopher N Hahn; Hamish S Scott Journal: Blood Adv Date: 2020-03-24
Authors: Tanmya Sharma; Justin G Brunet; Subia Tasneem; Stephanie A Smith; James H Morrissey; Catherine P M Hayward Journal: Int J Lab Hematol Date: 2021-06-29 Impact factor: 3.450