A significant proportion (overall ∼7%) of patients with myelodysplastic syndrome or myelodysplastic neoplasm (MDS) have a deleterious gene variant implicated in germ line predisposition disorder (GPD). The frequencies, types of GPDs, and the genetic alterations vary across different age ranges. Accurate identification of patients with GPD is of utmost importance as it necessitates modification to the management approaches. In addition to unusual clinical presentations such as younger age of onset and strong personal or family history of cancer, there are specific patterns of gene alterations that can be noted on routine somatic mutation panel and copy number testing that are highly suspicious for underlying GPDs. The proposed comprehensive diagnostic work-up can provide important clues to identify these patients.