P093 | ASSESSING HEREDITARY MYELOID NEOPLASMS THROUGH TARGETED NEXT GENERATION SEQUENCING PANEL DESIGN AND DEFINITION OF CLINICAL CRITERIA: A PILOT STUDY

Hereditary myeloid neoplasms with germline predisposition represent an emerging category within the spectrum of myelodysplastic and myeloproliferative syndromes. Early recognition of these conditions can significantly influence therapeutic decision-making, familial surveillance and the selection of related donors for hematopoietic stem cell transplantation. In this preliminary study, we designed a custom NGS panel targeting 98 genes of established clinical relevance. These include genes listed in the International Consensus and World Health Organization Classifications of hereditary myeloid disorders, genes involved in DNA repair-deficiency disorders and Fanconi anemia, as well as genes associated with syndromic conditions such as RASopathies, telomeropathies, inherited bone marrow failure syndromes and other cancer susceptibility syndromes. Bioinformatic optimization was performed through BAM file review to improve calculation of uniformity and coverage accuracy. To guide patient selection for genetic testing, we defined clinical history-based criteria: (i) diagnosis of a myeloid neoplasm before the age of 50, (ii) personal history of multiple hematologic and/or solid malignancies or (iii) family history of hematologic malignancies or solid tumors suggestive of an inherited cancer predisposition. The panel was validated in a cohort of 10 patients diagnosed with myelodysplastic syndrome or acute myeloid leukemia, all meeting at least one of the above criteria and aged between 45 and 78 years. NGS analysis identified germline variants classified as pathogenic or likely pathogenic in 7 patients, involving the genes BRCA1, ETV6, NF1, RUNX1, TET2 and TP53. Variants of uncertain significance were also detected in ACD, CHEK2, FANCM, FANCD2, MPL, NF1, PARN, PMS2 and SLX4. This pilot study supports the technical and clinical feasibility of integrating an extended NGS panel into routine hematologic diagnostics, guided by structured clinical criteria to improve the identification of patients with germline predisposition. Expansion of the study cohort, refinement of selection criteria and confirmation of germline variants through alternative specimens (e.g., saliva or T lymphocytes from peripheral blood) are currently underway, with the aim of promoting an integrated and personalized management of affected patients and at-risk family members.