Exploring a Unique RUNX1 Germline Mutation with a Double Nucleotide Variant: Implications for Clinical Significance

Abstract

Introduction: Myeloid neoplasms with germline RUNX1 mutation, an autosomal dominant disease characterized by thrombocytopenia and risk of hematologic malignancy, usually have a single nucleotide variant or insertions/deletions in RUNX1. Here, we present a patient with double nucleotide variant (DNV) in RUNX1. Case Presentation: The patient was a woman with progressive thrombocytopenia. She had a strong family history of thrombocytopenia and hematologic malignancies with a high fatality rate. We detected that genomic RUNX1 had consecutive DNV (c.352G>T and c.352-1 G>C) at its splice site, resulting in a frameshift mutation in exon 5. She rapidly progressed to a high-risk myeloid neoplasm owing to a germline RUNX1 mutation. Allogeneic transplantation successfully resulted in durable complete remission. Conclusion: To our knowledge, this is the first report of hereditary myeloid neoplasm carrying DNV in RUNX1. A family history of thrombocytopenia and the rapid malignant transformation suggests the potential pathogenic significance of the DNV.