Novel Candidate loci and Pathogenic Germline Variants Involved in Familial Hematological Malignancies Revealed by Whole-Exome Sequencing

Simple Summary Inherited predisposition to hematological malignancies is more common than previously perceived. The main objective of our study was to analyze the whole-exome sequencing data for the genomic characterization of sixteen patients with a strong family or personal onco-hematological history. When a duo analysis was performed, we detected pathogenic or likely pathogenic (P/LP) germline variants in four out of the six families studied. In the remaining four individuals, we detected three P/LP germline variants in genes with a potential role in cancer development. Next-generation sequencing strategies lead to the identification of novel candidate genes (NFATC2 and TC2N) potentially involved in the development of these germline syndromes. The recognition of predisposing variants is crucial for disease management and follow-up of affected patients and their relatives. 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.