Population Frequency of Fanconi Pathway Gene Variants and Their Association with Survival After Hematopoietic Cell Transplantation for Severe Aplastic Anemia. Biol Blood Marrow Transplant 2020 May;26(5):817-822
Date
01/27/2020Pubmed ID
31982544Pubmed Central ID
PMC7243455DOI
10.1016/j.bbmt.2020.01.011Scopus ID
2-s2.0-85082403233 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
Severe aplastic anemia (SAA) is most frequently immune-mediated; however, rare inherited bone marrow failure syndromes, such as Fanconi anemia (FA), may be causal and can present as aplastic anemia (AA). FA is primarily an autosomal recessive disorder caused by the presence of 2 pathogenic variants in a single FA/BRCA DNA repair pathway gene. Patients with SAA often undergo genetic testing during clinical evaluation that may identify single deleterious alleles in FA pathway genes. We quantified the rate of germline single deleterious alleles in 22 FA genes using both a general population database (3234 variants, 125,748 exomes) and in a cohort of patients with SAA undergoing hematopoietic cell transplantation (HCT) (21 variants in 730 patients). The variants were classified as deleterious using in silico tools (REVEL, MetaSVM, VEP) and database resources (ClinVar, LOVD-FA). We found similar rates of single deleterious alleles in FA genes in both groups (2.6% and 2.9%). The presence of a single deleterious variant in a gene for FA in SAA HCT recipients did not affect the overall survival after HCT (hazard ratio, 0.85; 95% CI, 0.37 to 1.95; P = 0.71), or post-HCT cancer risk (P = 0.52). Our results demonstrate that the identification of a germline monoallelic deleterious variant in an FA gene in patients with idiopathic SAA does not influence the outcome of HCT. Our findings suggest that there is no need for special treatment considerations for patients with SAA and a single deleterious FA allele identified on genetic testing.
Author List
McReynolds LJ, Wang Y, Thompson AS, Ballew BJ, Kim J, Alter BP, Hicks B, Zhu B, Jones K, Spellman SR, Wang T, Lee SJ, Savage SA, Gadalla SMAuthor
Tao Wang PhD Associate Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesAnemia, Aplastic
Fanconi Anemia
Gene Frequency
Hematopoietic Stem Cell Transplantation
Humans