Background: Hereditary myeloid malignancy syndromes (HMMS) are increasingly recognized in adult patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Timely diagnosis of HMMS is critical to ensure appropriate bone marrow donor selection, conditioning regimen intensity for allogeneic hematopoietic stem cell transplantation and surveillance for non-hematopoietic complications. Methods: A multidisciplinary team of hemato-oncologists, pathologists, and genetic counselors (GC) developed a systematic workflow for the HMMS workup of adults with myeloid neoplasms. Patients identified through this workflow met with a GC while receiving inpatient treatment. If genetic testing was deemed urgent due to an upcoming bone marrow transplant, potential donors were counselled concurrently with parallel genetic testing performed. Genetic test results were disclosed with appropriate post-test counseling by the primary hemato-oncologist and/or GC. Ancillary tests for inherited bone marrow failure syndromes, such as telomere length analysis and chromosomal breakage analysis were performed on a case-by-case basis. Results: Between May 1, 2020 to September 30, 2022, 21 patients were referred to a GC for HMMS workup. All were offered HMMS germline genetic testing; 19 completed testing with a targeted panel performed on DNA extracted from cultured fibroblasts and 1 completed testing on peripheral blood during AML remission due to poor fibroblast growth. Two patients had a pathogenic germline variant (PV) associated with HMMS and 2 had discrepant results between peripheral blood and skin fibroblasts, one with a PV identified in skin fibroblasts but not peripheral blood and one with a PV identified in peripheral blood but not confirmed in skin fibroblasts (Table 1). Two patients were found to be carriers—one for an autosomal recessive condition and one female for an x-linked condition. Eight (40%) had negative results and 17 variants of uncertain significance (VUS) were identified in eleven patients (55%). Conclusions: Our workflow highlights the importance of cultured fibroblasts for germline genetic testing in patients with myeloid neoplasms and exhibits the extensive coordination required for HMMS workup. Satisfactory fibroblast growth can be a hurdle in HMMS assessment. The diagnostic yield of a targeted gene panel in this setting is 10% with a VUS rate of 55%. Extensive research in HMMS is required to investigate the biological effects of the VUS detected.
Germline genetic testing for patients with myeloid malignancies.
PV: Pathogenic variant; LP: Likely pathogenic variant; VUS: Variant of Uncertain Significance
