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The familial occurrence of hematological malignancies has been underappreciated. Recent studies suggest that up to 15% of adults with myeloid neoplasms carry germline pathogenic variants in cancer-predisposing genes. This study aimed to identify the underlying germline predisposition variant in patients with a strong family or personal onco-hematological history using whole exome sequencing on sixteen uncharacterized individuals. It was carried out in two groups of patients, one with samples available from two affected relatives (Cohort A) and one with available samples from the index case (Cohort B). In Cohort A, six families were characterized. Two families shared variants in genes associated with DNA damage response and involved in cancer development ( CHEK2 and RAD54L ). Pathogenic or likely pathogenic germline variants were also found in novel candidate genes ( NFATC2 and TC2N ). In two families, any relevant pathogenic or likely pathogenic genomic variants were identified. In Cohort B, four additional index cases were analyzed. Three of them harbor clinically relevant variants in genes with a probable role in the development of inherited forms of hematological malignancies ( GATA1 , MSH4 and PRF1 ). Overall, whole exome sequencing is a useful approach to achieve a further characterization of these patients and their mutational spectra. Moreover, further investigations may help improve optimization for disease management of affected patients and their families.

FLT3 -internal tandem duplication (ITD) analysis is not typically performed in cDNA samples and is not considered an appropriate marker for monitoring measurable residual disease (MRD). The aims of this study were to compare FLT3 -ITD mutation analysis in DNA and cDNA samples at diagnosis and to demonstrate the usefulness of its expression measurement as an MRD marker after allogeneic stem cell transplantation (allo-HSCT) or FLT3 inhibitor (FLT3i) administration. A total of 46 DNA and cDNA diagnosis samples, 102 DNA and cDNA post-allo-HSCT samples from 34 patients and 37 cDNA samples from 7 patients with refractory/relapse AML treated with FLT3i were assessed for the FLT3 -ITD mutation through fragment analysis. In terms of sensitivity, the analysis of cDNA was superior to that of DNA, quantifying higher allelic ratio values in most cases at diagnosis, and thus optimizing the detection of minor clones and prognostic classification. Regarding the last sample before post-HSCT relapse, cDNA analysis anticipated relapse in most cases, unlike DNA analyses. With regard to the post-FLT3i follow-up, FLT3 -ITD expression was reduced after the first FLT3i cycle when the treatment was effective, whereas it was not reduced in refractory patients. FLT3 -ITD expression could be a useful additional biomarker at diagnosis and for the assessment of MRD after allo-HSCT and FLT3i in AML.