The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants
Mous, Rogier; .
(2020) Nature Communications, volume 11, issue 1, pp. 1 - 12
(Article)
Abstract
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
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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.
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Keywords: 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, General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: The authors thank the patients and their families for donating specimens for research in this study; Doriana Di Bella for her support in experimental procedures; Jessica Okosun for her critical reading of this manuscript; Sarah Charrot for her help in editing figures; and Tanya Cranfield, Charles Crawley, Raviv Dror, Ravi Kannan, Valarie Mialou, Corinne Pondarre, Elene Psiachou-Leonard, Graham R Standen, Angela Thomas, and Lisa Wolger for their contribution with patient samples. This study was predominantly funded by Bloodwise (14032), Medical Research Council (MR/PO18440/1) and Cancer Research UK (CR-UK) through a Clinical Research Fellowship awarded to K.T. N.H. and J.F.C. were supported by Core funding to the MRC Human Genetics Unit from the Medical Research Council. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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