Germline variants in acquired aplastic anemia: current knowledge and future perspectives

Abstract

Aplastic anemia (AA) is a disease characterized by hematopoiesis failure, bone marrow aplasia, and pancytopenia. It can be inherited or acquired. Although acquired AA is believed to be immune-mediated and random, new evidence suggests an underlying genetic predisposition. Besides confirmed genomic mutations that contribute to inherited AA (such as pathogenic mutations of TERT and TERC), germline variants, often in heterozygous states, also play an unignorable role in the onset and progression of acquired AA. These variants, associated with inherited bone marrow failure syndromes (IBMFS) and inborn errors of immunity (IEI), contribute to the disease possibly through mechanisms including gene homeostasis, DNA repair, and immune injury. This article explores the nuanced association between acquired AA and germline variants, detailed the clinical significance of germline variants in diagnosing and clinical management of this condition. More works are encouraged to better understand the role of immunogenic pathogenic variants and whether somatic mutation participate as secondary “hit” in the development of bone marrow failure.