RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML

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 HenryAmanda 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 Kr¨amer, Stefan Fröhling, Andrew H. Wei, Cecily Forsyth, Helen Mar Fan, Nicola K. Poplawski, Christopher N. Hahn, Hamish S. Scott

Research output: Contribution to journalArticlepeer-review


First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n 5 35) and published sporadic (n 5 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.

Original languageEnglish
Pages (from-to)1131-1144
Number of pages14
JournalBlood advances
Issue number6
StatePublished - 24 Mar 2020


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