RESUMEN
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.