Population frequency of Fanconi pathway gene variants and their association with survival after hematopoietic cell transplant for severe aplastic anemia

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 having two 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 transplant (HCT) (21 variants/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 an 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 (HR=0.85, 95% CI=0.37-1.95, p=0.71), or post-HCT cancer risk (p=0.52). Our results show that the identification of a germline monoallelic deleterious variant in an FA gene, in a patient 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. Copyright © 2020. Published by Elsevier Inc.

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