Real-world investigation of germ line predisposition to myelodysplastic syndromes

Abstract Follow-up of potential germ line variants revealed by diagnostic targeted sequencing (TS) for myelodysplastic syndromes (MDS) has been proposed by clinical guidelines. However, their feasibility and clinical yield in routine MDS practice remain uncertain. We evaluated the real-world applicability of systematic germ line follow-up in an unselected cohort of 716 patients (median age, 74 years) evaluated for MDS. Their diagnostic TS data were analyzed to identify variants in CEBPA, DDX41, ETV6, GATA2, and RUNX1 with a variant allele frequency of ≥35%. In total, 98 variants were identified in 87 (12.2%) patients. Germ line investigation was possible for 62 patients; for the remaining 25 without biobanked material, medical charts were reviewed. We identified pathogenic/likely pathogenic (P/LP) germ line variants in 19 patients (2.7%). Most P/LP variants were found in DDX41 (73.7%), followed by 10.5%, 10.5%, and 5.3% in RUNX1, GATA2, and ETV6, respectively, with germ line conversion rates between 5.4% and 93.3%. Patients with P/LP variants had a median age at diagnosis of 73 years, with male predominance (3.75:1). Most patients were diagnosed with MDS–excess blasts-1 (MDS-EB1) or MDS-EB2 (68.4%) and had normal cytogenetics (95%). A review of medical charts in younger patients (aged <50 years) revealed germ line predisposition in other genes in an additional 5 patients, revisiting the prevalence of predisposition to 3.4% overall and to 16.7% in those aged <50 years. Our results show that systematic germ line follow-up after diagnostic TS succeeds in identifying predisposition in nearly 3% of patients at a typical adult MDS clinic. Germ line testing for genes not routinely assessed by diagnostic TS is required in younger patients.