Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. The precise incidence of germline mutation carriers in the general population, or various clinically presenting patient groups, remain poorly defined for many reasons including; Somatic mutations in these genes are common in blood cancers; Our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Our knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins (including at both the germline and somatic allelic level) and the environment, and how these alter the clinical presentation of patients and their secondary leukemias is also incomplete. Principle among the many outstanding questions remaining for patients with these germline mutations as individuals, patient groups and their treating clinicians are; what is the natural course of the disease, what other symptoms may or will I develop and when, can you predict them, how can I prevent them and if they occur what is the best way to treat them. Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1,GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the WHO guidelines. The precise incidence of germline mutation carriers in the general population, or various clinically presenting patient groups, remain poorly defined for many reasons including; somatic mutations in these genes are common in blood cancers; our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Our knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins (including at both the germline and somatic allelic level) and the environment, and how these alter the clinical presentation of patients and their secondary leukemias is also incomplete. Principle among the many outstanding questions remaining for patients with these germline mutations as individuals, patient groups and their treating clinicians are; what is the natural course of the disease, what other symptoms may or will I develop and when, can you predict them, how can I prevent them and if they occur what is the best way to treat them. The resolution of many of the remaining clinical and biological questions, and effective evidence based treatment of patients with these inherited mutations, will depend on worldwide partnerships between patients, clinicians, diagnosticians and researchers to aggregate sufficient longitudinal clinical and laboratory data, and integrate this data with model systems.

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