RT Journal Article SR Electronic T1 Genomic Landscape of Patients with Germline RUNX1 Variants and Familial Platelet Disorder with Myeloid Malignancy JF bioRxiv FD Cold Spring Harbor Laboratory SP 2023.01.17.524290 DO 10.1101/2023.01.17.524290 A1 Kai Yu A1 Natalie Deuitch A1 Matthew Merguerian A1 Lea Cunningham A1 Joie Davis A1 Erica Bresciani A1 Jamie Diemer A1 Elizabeth Andrews A1 Alice Young A1 Frank Donovan A1 Raman Sood A1 Kathleen Craft A1 Shawn Chong A1 Settara Chandrasekharappa A1 Jim Mullikin A1 Paul P. Liu YR 2023 UL http://biorxiv.org/content/early/2023/01/17/2023.01.17.524290.abstract AB Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancies (FPDMM), which is characterized by thrombocytopenia and a life-long risk (35-45%) of hematological malignancies. We recently launched a longitudinal natural history study for patients with FPDMM at the NIH Clinical Center. Among 29 families with research genomic data, 28 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 24 of 54 (44.4%) non-malignant patients, somatic mutations were detected in at least one of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 7 other CHIP or AML driver genes (DNMT3A, TET2, NRAS, SETBP1, SF3B1, KMT2C, and LRP1B) were also found in more than one non-malignant patient. Moreover, three unrelated patients (one with myeloid malignancy) carried somatic mutations in NFE2, which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in elderly patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring dynamic changes of somatic mutations prospectively will benefit patients’ clinical management and reveal mechanisms for progression to myeloid malignancies.Key PointsComprehensive genomic profile of patients with FPDMM with germline RUNX1 mutations.Rising clonal hematopoiesis related secondary mutations that may lead to myeloid malignancies.Competing Interest StatementThe authors have declared no competing interest.