TY - JOUR
T1 - The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants
AU - Rio-Machin, Ana
AU - Vulliamy, Tom
AU - Hug, Nele
AU - Walne, Amanda
AU - Tawana, Kiran
AU - Cardoso, Shirleny
AU - Ellison, Alicia
AU - Pontikos, Nikolas
AU - Wang, Jun
AU - Tummala, Hemanth
AU - Al Seraihi, Ahad Fahad H.
AU - Alnajar, Jenna
AU - Bewicke-Copley, Findlay
AU - Armes, Hannah
AU - Barnett, Michael
AU - Bloor, Adrian
AU - Bödör, Csaba
AU - Bowen, David
AU - Fenaux, Pierre
AU - Green, Andrew
AU - Hallahan, Andrew
AU - Hjorth-Hansen, Henrik
AU - Hossain, Upal
AU - Killick, Sally
AU - Lawson, Sarah
AU - Layton, Mark
AU - Male, Alison M.
AU - Marsh, Judith
AU - Mehta, Priyanka
AU - Mous, Rogier
AU - Nomdedéu, Josep F.
AU - Owen, Carolyn
AU - Pavlu, Jiri
AU - Payne, Elspeth M.
AU - Protheroe, Rachel E.
AU - Preudhomme, Claude
AU - Pujol-Moix, Nuria
AU - Renneville, Aline
AU - Russell, Nigel
AU - Saggar, Anand
AU - Sciuccati, Gabriela
AU - Taussig, David
AU - Toze, Cynthia L.
AU - Uyttebroeck, Anne
AU - Vandenberghe, Peter
AU - Schlegelberger, Brigitte
AU - Ripperger, Tim
AU - Steinemann, Doris
AU - Wu, John
AU - Mason, Joanne
N1 - 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.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Adenosine Deaminase/genetics
KW - Axonemal Dyneins/genetics
KW - Cohort Studies
KW - Germ-Line Mutation
KW - Humans
KW - Leukemia, Myeloid, Acute/genetics
KW - Myelodysplastic Syndromes/genetics
KW - Nonsense Mediated mRNA Decay
KW - Pedigree
KW - Perforin/genetics
KW - Platelet Membrane Glycoproteins/genetics
KW - RNA Helicases/genetics
KW - Receptors, Interleukin-17/genetics
KW - Vesicular Transport Proteins/genetics
KW - Whole Exome Sequencing
UR - https://www.scopus.com/pages/publications/85081074310
U2 - 10.1038/s41467-020-14829-5
DO - 10.1038/s41467-020-14829-5
M3 - Article
C2 - 32098966
AN - SCOPUS:85081074310
SN - 2041-1723
VL - 11
SP - 1
EP - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1044
ER -