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

• Published in: Haematologica (Roma) 2024-09, Vol.109 (9), p.2778-2789
• Main Authors: Wang, Peicheng, Jiang, Wanzhi, Lai, Tianyi, Liu, Qi, Shen, Yingying, Ye, Baodong, Wu, Dijiong
• Format: Article
• Language: English
• Subjects: Anemia, Aplastic - diagnosis; Anemia, Aplastic - genetics; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Review
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2023.284312

Aplastic anemia (AA) is a disease characterized by failure of hematopoiesis, 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 a not negligible role in the onset and progression of acquired AA. These variants, associated with inherited bone marrow failure syndromes and inborn errors of immunity, 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, detailing the clinical significance of germline variants in diagnosing and managing this condition. More work is encouraged to better understand the role of immunogenic pathogenic variants and whether somatic mutations participate as secondary "hits" in the development of bone marrow failure.