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

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

<p dir="ltr">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) an...

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Main Author: Ana Rio-Machin (19686124) (author)
Other Authors: Tom Vulliamy (110425) (author), Nele Hug (16228043) (author), Amanda Walne (205621) (author), Kiran Tawana (19686127) (author), Shirleny Cardoso (19686130) (author), Alicia Ellison (19686133) (author), Nikolas Pontikos (4611358) (author), Jun Wang (5906) (author), Hemanth Tummala (209932) (author), Ahad Fahad H. Al Seraihi (19686136) (author), Jenna Alnajar (13227864) (author), Findlay Bewicke-Copley (485083) (author), Hannah Armes (19686139) (author), Michael Barnett (317282) (author), Adrian Bloor (3520115) (author), Csaba Bödör (483098) (author), David Bowen (89572) (author), Pierre Fenaux (751250) (author), Andrew Green (2960511) (author), Andrew Hallahan (11206439) (author), Henrik Hjorth-Hansen (3704839) (author), Upal Hossain (205601) (author), Sally Killick (89570) (author), Sarah Lawson (6194801) (author), Mark Layton (11457303) (author), Alison M. Male (19686142) (author), Judith Marsh (205617) (author), Priyanka Mehta (3213543) (author), Rogier Mous (15036779) (author), Josep F. Nomdedéu (19686145) (author), Carolyn Owen (19686148) (author), Jiri Pavlu (6330410) (author), Elspeth M. Payne (11424145) (author), Rachel E. Protheroe (19686151) (author), Claude Preudhomme (356069) (author), Nuria Pujol-Moix (805671) (author), Aline Renneville (114625) (author), Nigel Russell (3177729) (author), Anand Saggar (16045313) (author), Gabriela Sciuccati (19686154) (author), David Taussig (7944140) (author), Cynthia L. Toze (19686157) (author), Anne Uyttebroeck (160862) (author), Peter Vandenberghe (160870) (author), Brigitte Schlegelberger (136771) (author), Tim Ripperger (5612297) (author), Doris Steinemann (214253) (author), John Wu (681395) (author), Joanne Mason (3520556) (author), Paula Page (7389467) (author), Susanna Akiki (19684909) (author), Kim Reay (19686160) (author), Jamie D. Cavenagh (15010380) (author), Vincent Plagnol (50600) (author), Javier F. Caceres (5651266) (author), Jude Fitzgibbon (483100) (author), Inderjeet Dokal (205627) (author)
Published: 2020
Subjects:
Biological sciences
Genetics
Biomedical and clinical sciences
Clinical sciences
Familial Myeloid Malignancies
Acute Myeloid Leukemia (AML)
Germline Variants
Genetic Loci
Whole Exome Sequencing
Hematological Syndromes
Inherited Bone Marrow Failure
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Summary:<p dir="ltr">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, PRF1andSEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9,NAPRT1and 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.</p><h2>Other Information</h2><p dir="ltr">Published in: Nature Communications<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41467-020-14829-5" target="_blank">https://dx.doi.org/10.1038/s41467-020-14829-5</a></p>

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