Aplastic Anemia

A number sign (#) is used with this entry because of evidence that aplastic anemia can be associated with mutations in the interferon-gamma gene (IFNG; 147570), the NBS1 gene (602667), the PRF1 gene (170280), or the SBDS gene (607444).

Aplastic anemia may also result from bone marrow failure in patients with mutations in the TERT (187270) or the TERC (602322) gene: see PFBMFT1 (614742) and PFBMFT2 (614743).

Description

Aplastic anemia is a serious disorder of the bone marrow that affects between 2 and 5 persons per million per year. About 75% of these cases are classified as idiopathic (Young, 2000). In about 15% of cases a drug or infection can be identified that precipitates the aplasia, although why only some individuals are susceptible is unclear. In about 5 to 10% of patients, the aplastic anemia is constitutional--i.e., is familial or presents with one or more associated somatic abnormalities (summary by Vulliamy et al., 2002).

Molecular Genetics

Interferon-gamma mediates the final damage of the stem cell compartment in aplastic anemia. Dufour et al. (2004) studied the distribution of the VNDR 1349 polymorphism of IFNG (147570.0001) in 67 Caucasian patients with aplastic anemia and in normal controls. Homozygosity for allele 2 (12 repeats on each chromosome) or the 12 repeats on only 1 chromosome were significantly more frequent (p = 0.005 and 0.004, respectively) in patients versus controls. The polymorphism was equally distributed in aplastic anemia patients regardless of their response to immunosuppression. Dufour et al. (2004) concluded that homozygosity for 12 CA repeats at position 1349 of the IFNG gene is strongly associated with the risk of aplastic anemia in Caucasian subjects.

In an 11-year-old Japanese girl with aplastic anemia, Shimada et al. (2004) identified homozygosity for the I171V mutation in the NBS1 gene (602667.0007). The patient had no features of NBS (251260). Cytogenetic analysis of lymphoblastic cell lines from the patient showed a marked increase in numerical and structural chromosomal aberrations in the absence of clastogens, suggesting genomic instability.

Solomou et al. (2007) identified mutations in the PRF1 gene (170280.0011-170280.0013) in 5 unrelated patients with adult-onset aplastic anemia. Four of the 5 patients showed hemophagocytosis on bone marrow biopsy, but none had clinical manifestations of the hemophagocytosis syndrome (FHL2; 603553). Perforin protein levels in these patients were very low or absent, perforin granules were absent, and natural killer cell cytotoxicity was significantly decreased. Solomou et al. (2007) concluded that PRF1 gene alterations may explain aberrant proliferation and activation of cytotoxic T cells in aplastic anemia.

Calado et al. (2007) identified a heterozygous mutation in the SBDS gene (607444.0002) in 4 of 91 unrelated patients with aplastic anemia. These patients were younger on average (5 to 19 years) compared to other patients with aplastic anemia. Two mothers tested were carriers of the mutation; these 2 and another mother who was not tested had histories of subclinical mild anemia. Heterozygous mutation carriers had partial loss of SBDS protein expression, indicating haploinsufficiency. Although telomere shortening was observed in patients' granulocytes, lymphocytes had normal telomere length. Homozygous or compound heterozygous mutations in the SBDS gene result in Shwachman-Diamond syndrome (SDS; 260400), but none of the patients with aplastic anemia had pancreatic exocrine failure or skeletal anomalies as seen in SDS. One of the 4 probands was also heterozygous for a presumed pathogenic variant in the TERT gene.

Associations Pending Confirmation

For discussion of a possible association between aplastic anemia and variation in the MASTL gene, see 608221.0002.