Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) because of phenotypic heterogeneity. We curated germline genetic variants in 104 IBMFS-associated genes from exome sequencing performed on 732 patients who underwent hematopoietic cell transplant (HCT) between 1989 and 2015 for acquired SAA. Patients with pathogenic or likely pathogenic (P/LP) variants fitting known disease zygosity patterns were deemed unrecognized IBMFS. Carriers were defined as patients with a single P/LP variant in an autosomal recessive gene or females with an X-linked recessive P/LP variant. Cox proportional hazard models were used for survival analysis with follow-up until 2017. We identified 113 P/LP single-nucleotide variants or small insertions/deletions and 10 copy number variants across 42 genes in 121 patients. Ninety-one patients had 105 in silico predicted deleterious variants of uncertain significance (dVUS). Forty-eight patients (6.6%) had an unrecognized IBMFS (33% adults), and 73 (10%) were carriers. No survival difference between dVUS and acquired SAA was noted. Compared with acquired SAA (no P/LP variants), patients with unrecognized IBMFS, but not carriers, had worse survival after HCT (IBMFS hazard ratio [HR], 2.13; 95% confidence interval[CI], 1.40-3.24; P = .0004; carriers HR, 0.96; 95% CI, 0.62-1.50; P = .86). Results were similar in analyses restricted to patients receiving reduced-intensity conditioning (n = 448; HR IBMFS = 2.39; P = .01). The excess mortality risk in unrecognized IBMFS attributed to death from organ failure (HR = 4.88; P < .0001). Genetic testing should be part of the diagnostic evaluation for all patients with SAA to tailor therapeutic regimens. Carriers of a pathogenic variant in an IBMFS gene can follow HCT regimens for acquired SAA.

中文翻译：

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为了获得最佳的造血细胞移植结果，需要对严重再生障碍性贫血进行基因检测。


由于表型异质性，严重再生障碍性贫血 (SAA) 患者可能患有未被识别的遗传性骨髓衰竭综合征 (IBMFS)。我们对 1989 年至 2015 年间因获得性 SAA 接受造血细胞移植 (HCT) 的 732 名患者进行外显子组测序，从中筛选出了 104 个 IBMFS 相关基因的种系遗传变异。具有符合已知疾病接合性模式的致病性或可能致病性 (P/LP) 变异的患者被视为未识别的 IBMFS。携带者被定义为常染色体隐性基因中具有单一 P/LP 变异的患者或具有 X 连锁隐性 P/LP 变异的女性。 Cox 比例风险模型用于生存分析并随访至 2017 年。我们在 121 名患者的 42 个基因中发现了 113 个 P/LP 单核苷酸变异或小插入/缺失以及 10 个拷贝数变异。 91 名患者中有 105 名通过计算机预测存在不确定意义的有害变异 (dVUS)。 48 名患者 (6.6%) 的 IBMFS 未被识别（33% 为成人），73 名患者 (10%) 为携带者。 dVUS 和获得性 SAA 之间没有生存差异。与获得性 SAA（无 P/LP 变异）相比，未识别 IBMFS 的患者（而非携带者）HCT 后的生存率较差（IBMFS 风险比 [HR]，2.13；95% 置信区间 [CI]，1.40-3.24；P = .0004；运营商 HR，0.96；95% CI，0.62-1.50；仅限于接受降低强度训练的患者的分析结果相似（n = 448；HR IBMFS = 2.39；P = .01）。未识别的 IBMFS 中因器官衰竭导致的死亡风险过高（HR = 4.88；P < .0001）。基因检测应成为所有 SAA 患者诊断评估的一部分，以制定治疗方案。 IBMFS 基因致病性变异携带者可以遵循获得性 SAA 的 HCT 方案。