32. Genetic diagnosis of bone marrow failure syndromes: Strategies, yields, and challenges

      Bone marrow failure syndromes (BMFS) are a group of heterogeneous disorders often associated with germline changes in pediatric patients, known as inherited BMFS (IBMFS). We developed an NGS panel interrogating 159 genes associated with IBMFS, which evaluates sequence and copy number variations. Testing can be ordered as a comprehensive panel or several sub-panels with reflex to a larger panel. A total of 236 patients were tested and a definitive or possible molecular diagnosis was found in 39 cases (16.5%) including 2 patients carrying two potential genetic etiologies. Inconclusive findings were identified in 50 cases (21.1%) due to partial phenotypic overlap or limited variant evidence. The reported variants in 89 cases involve 44 genes with pathogenic variants most commonly seen in ELANE, followed by GATA2. The remaining 146 cases (61.9%) were negative with no variants, or only one variant in a recessive disorder gene. Our study affirms that targeted panels can facilitate the diagnosis of IBMFS; however, challenges remain. Most samples tested were blood, which may complicate variant interpretation if a latent/active myelodysplasia or leukemia is present, as was observed in two of these cases. Another challenge is secondary findings, such as a heterozygous pathogenic BRCA1 variant detected in a child with aplastic anemia. These challenges may be partially resolved by collecting additional familial and phenotypic information to help distinguishing acquired from inherited BMFS, obtaining appropriate tissue for testing, and refining the panel gene list or expanding to exome/genome sequencing to capture variants that may be missed by targeted analysis.
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