C084 | GEMMA PROJECT: GERMLINE GENETIC PROFILING TO ADVANCE PRECISION DIAGNOSTICS IN MYELOID NEOPLASMS AND BONE MARROW FAILURE SYNDROMES

Genetic germline characterization of myeloid neoplasms (MN) and bone marrow failures (BMF) has become increasingly important for precise diagnosis, but it also raises questions about managing carriers of germline variants. The widespread availability of genomic sequencing has improved their detection, though this process requires a dedicated diagnostic algorithm to determine who should be tested and how to accurately interpret the variants. We designed a hematologist-geneticist outpatient clinic (GEMMA project) at Rome Policlinico Tor Vergata, with the purpose of investigating conditions at risk of germline predisposition. A checklist was adopted for patient selection (Table 1). We aim at orientating physicians to implement germline testing and illustrate its potential for enabling personalized diagnostics in MN/BMF. From 03/2023 to 04/2025, we prospectively investigated 37 patients (median age 49 years, range 15-80 years, M|F ratio 0.9) with clinical suspicion of constitutional MN/BMF, and 30 family members. Initial diagnosis included acute myeloid leukemia in 15 cases, 7 myelodysplastic syndromes, 5 myeloproliferative neoplasms (MPN), 9 unexplained cytopenia, one aplastic anemia and one incidental finding in asymptomatic subject. Exome sequencing targeting 330 MN/BMF associated genes was performed using DNA from CD3+ cells in 34 cases and cultured skin fibroblasts in 3 cases. Family members were evaluated using DNA from peripheral blood mononuclear cells, with the germline nature confirmed through familial variant segregation. Genetic testing identified MN/BMF familial predisposition in 10/37 patients, an unexpectedly high proportion (27.0%): 3 DDX41 mutated MN, 2 GATA2 deficiencies, 2 SH2B3 mutated MPN, one telomere biology disorder (TERC), one SAMD9 syndrome and one Fanconi anemia (FANCA). Four family members were identified as asymptomatic carriers (2 SH2B3, GATA2 and TERC), stressing the critical role of genetic counseling and personalized monitoring strategies. We highlight the importance of accurately selecting adult MN/BMF cases to maximize the yield of germline testing and increase the detection of clinically relevant variants. This approach enabled the identification of actionable variants, with direct implications for patient management. As germline testing becomes increasingly integrated into clinical care for patients and their families, we emphasize the critical role of geneticists in effectively communicating the implications of results.