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Presentation Details
| Identification of a Proposed Novel Pathogenic MYH-9 Mutation in a Family with Dual Diagnosis of Von Willebrand Disease and Suspected MYH9-Related Disease Kawana Simon1, Radha Vyas1, Colleen Ciccosanti2. 1Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.2Division of Hematology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA |
Abstract
Background: MYH9-related disease (MYH9-RD) is a rare autosomal dominant platelet disorder that results from pathogenic variants in the MYH9 gene, which encodes non-muscle myosin heavy chain IIA1. Clinically, affected individuals exhibit persistent macrothrombocytopenia and Döhle-like inclusions, variable bleeding phenotypes, and may have associated sensorineural hearing loss, cataracts, and/or nephropathy2,3. Accurate recognition is essential to guide appropriate management and ensure long-term monitoring for potential systemic complications. Case: A 30-year-old male with lifelong easy bruising, prolonged bleeding with minor injuries, chronic gingival bleeding, weekly epistaxis, and prolonged bleeding after dental extraction was evaluated by hematology. His mother, a 66-year-old-female, carried a diagnosis of Von Willebrand Disease (VWD) and chronic mild thrombocytopenia. She reported a history of spontaneous bruising, prolonged bleeding with minor injuries, chronic gingival bleeding, post-tonsillectomy bleeding, menorrhagia, and postpartum hemorrhage. All four of her children reportedly have chronic thrombocytopenia, some with apparent bleeding phenotypes. Given the above history, he underwent a comprehensive hemostatic evaluation, which revealed chronic mild macrothrombocytopenia, mildly abnormal platelet aggregometry, decreased Von Willebrand Factor (VWF) antigen and ristocetin cofactor activity with a ratio <0.7, and decreased PAI-1 activity. Due to the complexity of the case and suspicion of a possible inherited thrombocytopenia syndrome, genetic testing was pursued. Testing of the VWF gene revealed a pathogenic heterozygous deletion in chromosome 12, g.6257211-6234858, a heterozygous variant of uncertain significance (VUS) in exon 8, c.974G>T, p.Cys325Phe, and the benign D1472H variant. Testing also revealed a missense VUS in exon 28, the tail domain, of the MYH9 gene, c.3679G>T, p.Gly1227Trp. Subsequent testing in his mother revealed the same MYH9 variant. Discussion: Given the multigenerational pattern of chronic mild thrombocytopenia and bleeding manifestations in this family, it is suspected that this missense variant in the tail domain of MYH9 may be a pathogenic variant. Many mutations in the MYH9 gene leading to macrothrombocytopenia have been reported4. Motor domain variants are associated with more significant thrombocytopenia, early-onset sensorineural hearing loss, and progressive renal disease, whereas tail domain variants typically result in milder clinical manifestations5,6. The relatively mild phenotype observed in this case aligns with the expected manifestations of a tail domain mutation. Emerging mechanistic data show that MYH9 mutations contribute to bleeding not only through platelet abnormalities, but also through impaired endothelial VWF biology. Endothelial expression of the E1841K MYH9 mutant disrupts Weibel–Palade body trafficking, reduces cAMP-mediated VWF release, and prolongs bleeding time despite normal platelet parameters7. This data suggests complex interactions between MYH9 and VWF in the coagulation system and highlights an area in need of further investigation. Conclusions: MYH9-related disease should be considered in individuals presenting with lifelong macrothrombocytopenia, particularly when there is evidence of multigenerational inheritance. Prompt identification reduces the risk of misdiagnosis and inappropriate therapies, allows for prioritization of bleeding risk reduction, and facilitates appropriate monitoring for renal, auditory, and ophthalmologic complications.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.