The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

Nat Commun. 2020 Feb 25;11(1):1044. doi: 10.1038/s41467-020-14829-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adenosine Deaminase / genetics
  • Axonemal Dyneins / genetics
  • Cohort Studies
  • Germ-Line Mutation*
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Myelodysplastic Syndromes / genetics*
  • Nonsense Mediated mRNA Decay
  • Pedigree
  • Perforin / genetics
  • Platelet Membrane Glycoproteins / genetics
  • RNA Helicases / genetics
  • Receptors, Interleukin-17 / genetics
  • Vesicular Transport Proteins / genetics
  • Whole Exome Sequencing


  • Adaptor Proteins, Signal Transducing
  • IL17RA protein, human
  • PRF1 protein, human
  • Platelet Membrane Glycoproteins
  • Receptors, Interleukin-17
  • SEC23B protein, human
  • SH2B3 protein, human
  • Vesicular Transport Proteins
  • platelet membrane glycoprotein VI
  • Perforin
  • DHX34 protein, human
  • ADA protein, human
  • Adenosine Deaminase
  • RNA Helicases
  • Axonemal Dyneins
  • DNAH9 protein, human