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.

中文翻译：

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范可尼途径基因变异的群体频率及其与严重再生障碍性贫血造血细胞移植后生存的关系。


严重再生障碍性贫血 (SAA) 最常见的是免疫介导的；然而，罕见的遗传性骨髓衰竭综合征，例如范可尼贫血 (FA)，可能是病因，并可能表现为再生障碍性贫血 (AA)。 FA 主要是一种常染色体隐性遗传疾病，由单个 FA/BRCA DNA 修复途径基因中存在 2 个致病变异引起。 SAA 患者经常在临床评估期间接受基因检测，可能会识别 FA 通路基因中的单个有害等位基因。我们使用一般人群数据库（3234 个变异，125,748 个外显子组）和接受造血细胞移植 (HCT) 的 SAA 患者队列（730 名患者中的 21 个变异）量化了 22 个 FA 基因中种系单一有害等位基因的比率。使用计算机工具（REVEL、MetaSVM、VEP）和数据库资源（ClinVar、LOVD-FA）将这些变体归类为有害变体。我们发现两组 FA 基因中单个有害等位基因的比率相似（2.6% 和 2.9%）。 SAA HCT 受者中 FA 基因中存在单一有害变异并不影响 HCT 后的总生存率（风险比，0.85；95% CI，0.37 至 1.95；P = 0.71）或 HCT 后癌症风险（ P = 0.52）。我们的结果表明，特发性 SAA 患者 FA 基因中种系单等位基因有害变异的鉴定不会影响 HCT 的结果。我们的研究结果表明，对于 SAA 和基因检测中发现的单个有害 FA 等位基因的患者，无需特殊治疗考虑。