The inclusion of familial myeloid malignancies as a separate disease entity in the
revised WHO classification has renewed efforts to improve the recognition and management
of this group of at risk individuals. Here we report a cohort of 86 acute myeloid
leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline
variants in 16 previously defined loci (57%). Whole exome sequencing in a further
37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci,
including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and
SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9,
NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited
forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel
insights into the etiology of myeloid malignancies and provide a framework to prioritize
variants for inclusion into routine diagnostics and patient management.
