Prevalence and clinical expression of germline predisposition to myeloid neoplasms in adults with marrow hypocellularity.

Systematic studies of germline genetic predisposition to myeloid neoplasms are still limited in adult patients. In this work, we performed germline and somatic targeted sequencing in a large cohort of adult patients with cytopenia and hypoplastic bone marrow to study germline predisposition variants and their clinical correlates. The study population included 402 consecutive adult patients investigated for unexplained cytopenia and reduced age-adjusted bone marrow cellularity. Germline mutation analysis was performed using a panel of 60 genes, and variants were interpreted according to the ACMG/AMP guidelines; somatic mutation analysis was performed using a panel of 54 genes. Twenty-seven out of 402 (6.7%) subjects carried germline variants causative of a predisposition syndrome/disorder. The most frequent predisposition disorders were DDX41-associated predisposition, Fanconi anemia, GATA2-deficiency syndrome, severe congenital neutropenia, RASopathy and Diamond-Blackfan anemia. Eighteen of 27 patients (67%) with causative germline genotype were diagnosed with myeloid neoplasm, whereas the remaining with cytopenia of undetermined significance. Subjects with predisposition syndrome/disorder were younger than the remaining ones (P=.03) and had higher risk of severe or multiple cytopenias and advanced myeloid malignancy (OR ranging from 2.51 to 5.58). In patients with myeloid neoplasm, causative germline mutations were associated with increased risk of progression into acute myeloid leukemia (HR=3.92, P=.008). Family history of cancer or personal history of multiple tumors, did not show significant association with a predisposition syndrome/disorder. The findings of this study unveil the spectrum, clinical expressivity and prevalence of germline predisposition mutations in an unselected cohort of adult patients with cytopenia and hypoplastic bone marrow.