Anemia, Sideroblastic, 4

A number sign (#) is used with this entry because of evidence that sideroblastic anemia-4 (SIDBA4) is caused by heterozygous mutation in the HSPA9 gene (600548) on chromosome 5q31. The presence of an HSPA9 variant in trans may be required for expression of the clinical phenotype (see MOLECULAR GENETICS).

Description

Sideroblastic anemia comprises a heterogeneous group of inherited and acquired disorders characterized by ineffective erythropoiesis. Anemia, if present, may be microcytic or macrocytic. Sometimes a dimorphic picture is observed in which 2 populations of erythrocytes can be detected in peripheral blood smears. The presence of ringed sideroblasts (erythroblasts containing pathologic mitochondrial iron deposits) in bone marrow is pathognomonic for sideroblastic anemia (van Waveren Hogervorst et al., 1987; Schmitz-Abe et al., 2015).

For a discussion of genetic heterogeneity of sideroblastic anemia, see SIDBA1 (300751).

Clinical Features

Van Waveren Hogervorst et al. (1987) studied a large Dutch family in which an 81-year-old mother and her 45-year-old son had sideroblastic anemia diagnosed on the basis of the finding of ringed sideroblasts in bone marrow preparations. Both also had a bimodal erythrocyte volume distribution curve and a dimorphic appearance of red cells on smear. The pattern of inheritance of the morphologic abnormality, which was found in 22 of 49 members of the family, was clearly autosomal dominant. Bimodality of red cell volume is usually taken as an indication of the heterozygous state of X-linked sideroblastic anemia (300751). The observations in this family indicate that this may not always be justified.

Amos et al. (1988) reported a 25-year-old man with sideroblastic anemia and dimorphic peripheral blood films. A bone marrow biopsy showed that 95% of erythrocytes were ringed sideroblasts. The father had a less severe phenotype, with 6% ringed sideroblasts on bone marrow aspirate and a small population of hypochromic, microcytic red cells on peripheral smear. Anemia was not present in the father. The sideroblastic trait appeared to have an autosomal inheritance pattern.

Mapping

In a Dutch kindred segregating autosomal dominant mild congenital sideroblastic anemia, originally reported by van Waveren Hogervorst et al. (1987), Schmitz-Abe et al. (2015) performed linkage analysis and mapped the disease to chromosome 5q with a lod score of 3.00. A second family (family B) with sideroblastic anemia also showed dominant linkage to 5q, with a lod score of 1.20 (cumulative lod, 4.20). A 26-Mb candidate interval was defined (chr5:134,164,092-160,559,870; GRCh37), encompassing 241 genes.

Molecular Genetics

In a 4-generation Dutch kindred with mild congenital sideroblastic anemia mapping to chromosome 5q, originally reported by van Waveren Hogervorst et al. (1987), Schmitz-Abe et al. (2015) analyzed the candidate gene HSPA9 (600548) and identified a heterozygous 2-bp deletion (600548.0001) that segregated with the disease. Affected individuals from a second family (family B) with sideroblastic anemia mapping to 5q were heterozygous for an in-frame 6-bp deletion in HSPA9 (600548.0002). Sequencing of 88 other probands with congenital sideroblastic anemia revealed 9 additional patients with at least 1 HSPA9 variant with a frequency of less than 1% in the Exome Variant database; Schmitz-Abe et al. (2015) stated that the mutation burden alone was sufficient to implicate HSPA9 mutations as causative. The authors further noted that some families with HSPA9 variants appeared to demonstrate autosomal recessive inheritance, and observed that the minor T allele of the synonymous SNP rs10117, which correlated with reduced mRNA expression, was present in trans in 9 of 10 affected individuals from the first 2 families. Phenotype permutation analysis of 21 individuals heterozygous for a presumptive HSPA9 coding mutation yielded a p value less than 0.07, suggesting that the rs10117 T allele or a linked variant determines expression of the HSPA9 sideroblastic anemia phenotype in patients with a single unambiguously deleterious allele. Schmitz-Abe et al. (2015) concluded that this form of sideroblastic anemia is an autosomal recessive disorder, with a pseudodominant pattern of inheritance in some families.