Molecular approach to cytopenia and bone marrow failure

Abstract Cytopenias are common in the adult population, with increasing recognition of clonal hematopoiesis and inherited syndromes due to widespread molecular testing. Clonal hematopoiesis is a premalignant spectrum of disorders characterized by a somatic myeloid mutation, including clonal hematopoiesis of indeterminate potential and clonal cytopenia of uncertain significance. Inherited bone marrow failure syndromes (IBMFS) can also be found during workup of incidental cytopenias, even in the absence of other syndromic associations. In clonal cytopenia of uncertain significance, the overall risk of progressing to a myeloid neoplasm can be affected by the type of mutation, number of mutations, and variant allele frequency. Prognostication systems, such as the Clonal Hematopoiesis Risk Score, MN-predict, and Clonal Cytopenia Risk Score, can help determine the risk of malignant progression. Context-dependent factors like chemotherapy, radiation, and smoking can influence this risk. For suspected IBFMS, workup typically includes telomere length testing and chromosomal breakage analysis, along with comprehensive germline testing. If IBMFS is confirmed, further testing may be indicated based on the syndrome, as patients are often at risk of other organ dysfunction and malignancies. In these patients, stem cell transplantation may be indicated.