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Integration of a Bone Marrow Failure Germline Panel into the Comprehensive Clinical Genomics Pipeline at St. Jude Children’s Research Hospital 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Bone marrow failure (BMF) is characterized by the bone marrow’s inability to produce sufficient blood cells, leading to cytopenias in one or more hematopoietic lineages. These disorders can be either acquired or inherited, with inherited bone marrow failure syndromes often manifesting in childhood or adolescence. Advances in genomic characterization have significantly improved the diagnosis and management of BMF, offering substantial benefits for patients and their families by enabling early disease detection and helping to distinguish overlapping features with other conditions. However, diagnostic challenges are compounded by time-consuming tests. The implementation of a gene panel for BMF addresses these limitations by providing a comprehensive, efficient, and rapid method for identifying pathogenic variants across multiple genes, thereby improving diagnostic precision and clinical decision-making.

Methods:
Germline BMF testing using whole-genome and exome sequencing targeting 155 BMF-associated genes was implemented at our institution in April 2023. Patients identified by their clinicians as having clinical features of bone marrow failure or related hematologic disorders were selected for genetic testing. Genetic counselors provided pre-test counseling, obtained informed consent, and facilitated interpretation and post-test counseling upon return of germline results. To date, 56 patients have undergone testing, with samples obtained from direct skin biopsies (71%) or blood draws (29%). Additionally, 17 patients with a confirmed or suspected cancer diagnosis also underwent complementary testing using a 115-gene cancer predisposition panel.

Results:
Initial presentations included 10 BMF syndromes (Diamond-Blackfan anemia, GATA2 deficiency, SAMD9/9L syndromes), 28 aplastic anemia/cytopenia cases, 9 acute myeloid leukemias, 1 B-acute lymphoblastic leukemia, 2 myelodysplastic syndromes and 6 treatment related hematologic disorders after solid or brain tumors.

Genetic testing identified 17 germline variants classified as likely/pathogenic in 15 patients. The affected genes included BLM, BRCA2, BRIP1, CHEK2, CTC1, FANCG, MECOM, MPL, POT1, RBM8A, RPL15, and SAMD9L, with multiple mutations detected in GATA2 (n=2) and FANCA (n=3). Notably, whole-genome sequencing identified two exon-level deletions in FANCA and a whole-gene deletion in RPL15, underscoring the value of comprehensive genomic analysis. Moreover, among the 17 patients evaluated with the cancer predisposition panel, pathogenic variants in RECQL4 and NTHL1 were found in 2 patients.

Molecular diagnostics provided confirmatory diagnoses and revealed incidental findings in 9 patients. Three patients, including 2 initially diagnosed with AML and 1 with pancytopenia, were reclassified as Fanconi anemia following the identification of pathogenic FANCA/G variants. One patient, initially diagnosed with pancytopenia, received a confirmatory diagnosis of dyskeratosis congenita following the identification of a novel homozygous variant in the CTC1 gene. Similarly, another patient presenting with cytopenia was confirmed to have MECOM-associated syndrome. Further, a patient with retinoblastoma and delayed count recovery was diagnosed with Bloom syndrome due to a homozygous BLM variant. Incidental findings in 3 patients included variants associated with cancer predisposition in BRCA2, POT1 and CHEK2.

Conclusion:
The implementation of germline testing at our institution has demonstrated its clinical utility in refining diagnoses and guiding patient management in individuals with cancer predisposition and now with bone marrow failure and related conditions. Germline testing clarified diagnoses in 11% of patients (6/56), confirming conditions such as Fanconi anemia, dyskeratosis congenita, and Bloom syndrome. Additionally, incidental findings in genes predisposing to cancer were identified in 5% of patients (3/56). Overall, pathogenic variants were detected in 27% (15/56) of cases, highlighting the diagnostic value of genomic testing. In a subset of patients, additional testing with a cancer predisposition panel detected clinically significant variants in 12% (2/17), providing critical insights for personalized risk assessment and family planning. This study highlights the critical role of germline genetic testing in improving diagnostic accuracy and optimizing treatment for patients with complex hematologic and oncologic presentations.

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