{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:19:15Z","timestamp":1768504755180,"version":"3.49.0"},"posted":{"date-parts":[[2023,1,17]]},"group-title":"Genomics","reference-count":51,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,1,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Germline\n                  <jats:italic>RUNX1<\/jats:italic>\n                  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\n                  <jats:italic>RUNX1<\/jats:italic>\n                  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.\n                  <jats:italic>BCOR<\/jats:italic>\n                  was the most frequently mutated gene (in 9 patients), and multiple\n                  <jats:italic>BCOR<\/jats:italic>\n                  mutations were identified in 4 patients. Mutations in 7 other CHIP or AML driver genes (\n                  <jats:italic>DNMT3A, TET2, NRAS, SETBP1, SF3B1, KMT2C<\/jats:italic>\n                  , and\n                  <jats:italic>LRP1B<\/jats:italic>\n                  ) were also found in more than one non-malignant patient. Moreover, three unrelated patients (one with myeloid malignancy) carried somatic mutations in\n                  <jats:italic>NFE2<\/jats:italic>\n                  , 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\n                  <jats:italic>RUNX1<\/jats:italic>\n                  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\u2019 clinical management and reveal mechanisms for progression to myeloid malignancies.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        Comprehensive genomic profile of patients with FPDMM with germline\n                        <jats:italic>RUNX1<\/jats:italic>\n                        mutations.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Rising clonal hematopoiesis related secondary mutations that may lead to myeloid malignancies.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2023.01.17.524290","type":"posted-content","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T04:35:05Z","timestamp":1674016505000},"source":"Crossref","is-referenced-by-count":5,"title":["Genomic Landscape of Patients with Germline\n                  <i>RUNX1<\/i>\n                  Variants and Familial Platelet Disorder with Myeloid Malignancy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2561-8160","authenticated-orcid":false,"given":"Kai","family":"Yu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0146-1162","authenticated-orcid":false,"given":"Natalie","family":"Deuitch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Merguerian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lea","family":"Cunningham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joie","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erica","family":"Bresciani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamie","family":"Diemer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Andrews","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Young","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Donovan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raman","family":"Sood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen","family":"Craft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shawn","family":"Chong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Settara","family":"Chandrasekharappa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0825-3750","authenticated-orcid":false,"given":"Jim","family":"Mullikin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul P.","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023011910502040000_2023.01.17.524290v1.1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-12-689109"},{"key":"2023011910502040000_2023.01.17.524290v1.2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-687830"},{"key":"2023011910502040000_2023.01.17.524290v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/13793"},{"key":"2023011910502040000_2023.01.17.524290v1.4","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000901"},{"key":"2023011910502040000_2023.01.17.524290v1.5","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminhematol.2014.08.001"},{"key":"2023011910502040000_2023.01.17.524290v1.6","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminhematol.2016.11.003"},{"key":"2023011910502040000_2023.01.17.524290v1.7","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019003357"},{"key":"2023011910502040000_2023.01.17.524290v1.8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI147898"},{"key":"2023011910502040000_2023.01.17.524290v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.236"},{"key":"2023011910502040000_2023.01.17.524290v1.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan4673"},{"key":"2023011910502040000_2023.01.17.524290v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.01.011"},{"key":"2023011910502040000_2023.01.17.524290v1.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1701719"},{"key":"2023011910502040000_2023.01.17.524290v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-019-0247-5"},{"key":"2023011910502040000_2023.01.17.524290v1.14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-03-631747"},{"key":"2023011910502040000_2023.01.17.524290v1.15","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000989"},{"key":"2023011910502040000_2023.01.17.524290v1.16","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-04-641100"},{"key":"2023011910502040000_2023.01.17.524290v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2023011910502040000_2023.01.17.524290v1.18","doi-asserted-by":"publisher","DOI":"10.1101\/gr.6861907"},{"key":"2023011910502040000_2023.01.17.524290v1.19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004873"},{"key":"2023011910502040000_2023.01.17.524290v1.20","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.4.1364"},{"key":"2023011910502040000_2023.01.17.524290v1.21","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24703"},{"key":"2023011910502040000_2023.01.17.524290v1.22","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1301689"},{"key":"2023011910502040000_2023.01.17.524290v1.23","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-017-0424-2"},{"key":"2023011910502040000_2023.01.17.524290v1.24","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14454"},{"key":"2023011910502040000_2023.01.17.524290v1.25","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020010402"},{"key":"2023011910502040000_2023.01.17.524290v1.26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-09-875047"},{"key":"2023011910502040000_2023.01.17.524290v1.27","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004088"},{"key":"2023011910502040000_2023.01.17.524290v1.28","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0151"},{"key":"2023011910502040000_2023.01.17.524290v1.29","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-11-254664"},{"key":"2023011910502040000_2023.01.17.524290v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.12.014"},{"key":"2023011910502040000_2023.01.17.524290v1.31","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-03-490425"},{"key":"2023011910502040000_2023.01.17.524290v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.04.008"},{"key":"2023011910502040000_2023.01.17.524290v1.33","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408617"},{"key":"2023011910502040000_2023.01.17.524290v1.34","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409405"},{"key":"2023011910502040000_2023.01.17.524290v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2819-2"},{"key":"2023011910502040000_2023.01.17.524290v1.36","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-019-6041-2"},{"key":"2023011910502040000_2023.01.17.524290v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/nature12477"},{"key":"2023011910502040000_2023.01.17.524290v1.38","doi-asserted-by":"publisher","DOI":"10.1101\/gr.226845.117"},{"key":"2023011910502040000_2023.01.17.524290v1.39","doi-asserted-by":"publisher","DOI":"10.1186\/2050-7771-2-4"},{"key":"2023011910502040000_2023.01.17.524290v1.40","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-018-2976-8"},{"key":"2023011910502040000_2023.01.17.524290v1.41","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700883"},{"key":"2023011910502040000_2023.01.17.524290v1.42","doi-asserted-by":"publisher","DOI":"10.1136\/jclinpath-2019-205895"},{"key":"2023011910502040000_2023.01.17.524290v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2005"},{"key":"2023011910502040000_2023.01.17.524290v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1909"},{"key":"2023011910502040000_2023.01.17.524290v1.45","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-12-399337"},{"key":"2023011910502040000_2023.01.17.524290v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.027"},{"key":"2023011910502040000_2023.01.17.524290v1.47","doi-asserted-by":"publisher","DOI":"10.1172\/JCI46129"},{"key":"2023011910502040000_2023.01.17.524290v1.48","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1133"},{"key":"2023011910502040000_2023.01.17.524290v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21588-4"},{"key":"2023011910502040000_2023.01.17.524290v1.50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1805662115"},{"key":"2023011910502040000_2023.01.17.524290v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.108"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.01.17.524290","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:08:31Z","timestamp":1768450111000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.01.17.524290"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,17]]},"references-count":51,"URL":"https:\/\/doi.org\/10.1101\/2023.01.17.524290","relation":{},"subject":[],"published":{"date-parts":[[2023,1,17]]},"subtype":"preprint"}}