Hereditary platelet disorders associated with germline variants in RUNX1, ETV6 and ANKRD26.

Hereditary platelet disorders (HPD) are a group of blood disorders with variable severity and clinical impact. Although phenotypically there is much overlap, known genetic causes are many, prompting the curation of multi-gene panels for clinical use, which are being deployed in increasingly large scale populations to uncover missing heritability more efficiently. For some of these disorders, in particular RUNX1, ETV6 and ANKRD26, pathogenic germline variants in these genes also come with a risk of development of hematological malignancy. While they may initially present as similarly mild-moderate thrombocytopenia, each of these three disorders have distinct penetrance of hematological malignancy and a different range of somatic alterations associated with malignancy development. As our ability to diagnose HPDs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients and how to optimize management and surveillance of patients and carriers who have not developed malignancy. The volume of genetic information now being generated has created new challenges in how to accurately assess and report identified variants. The answers to all of these questions involve international initiatives on rare disease to better understand the biology of these disorders and design appropriate models and therapies for pre-clinical testing and clinical trials. Partnered with this are continued technological developments, including rapid sharing of genetic variant information and automated integration with variant classification relevant data such as high throughput functional data. Collective progress in this area will drive timely diagnosis and, in time, leukemia preventative therapeutic interventions.