Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages. Blood 2022 Dec 15;140(24):2533-2548
Date
08/16/2022Pubmed ID
35969835Pubmed Central ID
PMC9918848DOI
10.1182/blood.2022015790Scopus ID
2-s2.0-85143522737 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
The frequency of pathogenic/likely pathogenic (P/LP) germ line variants in patients with myelodysplastic syndrome (MDS) diagnosed at age 40 years or less is 15% to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole-exome sequencing of peripheral blood samples from 404 patients with MDS and their related donors before allogeneic hematopoietic stem cell transplantation. Single-nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germ line status was established by the presence of a variant in the patient and related donor or for those seen previously only as germ line alleles. We identified P/LP germ line variants in 28 of 404 patients with MDS (7%), present within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs 25%; P = .04). There was no statistically significant difference in outcome parameters between patients with and without a germ line variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in 5 patients aged less than 40 years, whereas variants in DDX41 (n = 4), telomere biology disorder genes (n = 2), and general tumor predisposition genes (n = 17) were found in patients aged more than 40 years. If presumed germ line variants were included, the yield of P/LP variants would increase to 11%, and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germ line variants in our study supports comprehensive germ line genetic testing for all patients with MDS regardless of their age at diagnosis.
Author List
Feurstein S, Trottier AM, Estrada-Merly N, Pozsgai M, McNeely K, Drazer MW, Ruhle B, Sadera K, Koppayi AL, Scott BL, Oran B, Nishihori T, Agrawal V, Saad A, Lindsley RC, Nakamura R, Kim S, Hu Z, Sobecks R, Spellman S, Saber W, Godley LAAuthors
Soyoung Kim PhD Associate Professor in the Institute for Health and Equity department at Medical College of WisconsinWael Saber MD, MS Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultGenetic Predisposition to Disease
Genetic Testing
Germ Cells
Germ-Line Mutation
Humans
Myelodysplastic Syndromes
