Inherited bone marrow failure syndromes (IBMFS) are a heterogenous group of diseases caused by pathogenic germline variants in key pathways associated with haematopoiesis and genomic stability. Germline variants in IBMFS-related genes are known to reduce the fitness of hematopoietic stem and progenitor cells (HSPC), which has been hypothesized to drive clonal selection in these diseases. In many IBMFS, somatic mosaicism predominantly impacts cells by two distinct mechanisms, with contrasting effects. An acquired variation can improve cell fitness towards baseline levels, providing rescue of a deleterious phenotype. Alternatively, somatic mosaicism may result in a fitness advantage that results in malignant transformation. This review will describe these phenomena in IBMFS and delineate their relevance for diagnosis and clinical management. In addition, we will discuss which samples and methods can be used for detection of mosaicism according to clinical phenotype, type of mosaicism, and sample availability.
Keywords: Clonal haematopoiesis; Inherited bone marrow failure syndromes; Mosaicism.
Published by Elsevier Ltd.