Hereditary Hematologic Malignancies and Where to Find Them

Although hematologic malignancies are mainly sporadic, an increasing number of cases result from an inherited predisposition. The current landscape of hematologic diagnostics includes next-generation sequencing and the integration of myeloid neoplasms with germline predisposition in the World Health Organization and International Consensus Classification. Identifying inherited hematologic malignancies is challenging because of overlapping somatic mutations, clonal hematopoiesis, varying penetrance, and acquired somatic genetic rescue. Constitutional genetic testing requires a thorough strategy. This includes choosing an optimal tissue sample to avoid contamination with malignant blasts or donor chimerism following transplantation. When multigene panels yield indeterminate results, orthogonal technologies, functional analyses, and reflex to exome or genome sequencing are essential. Molecular confirmation is crucial to apply genomics in clinical practice by avoiding unintended transplantations with donors who carry pathogenic variants, adjusting transplant conditioning to reduce toxicity in diseases with DNA repair defects and telomere biology abnormalities, and implementing surveillance and cascade screening based on the syndromes’ characteristics. This review highlights major hereditary hematologic malignancy syndromes, describes clinical alarm signs that warrant further investigation, and provides an algorithm for genetic and hematologic practice.