Two novel variants in the SLC25A38 gene among two Iranian families with congenital sideroblastic anemia

Congenital Sideroblastic Anemia (CSA) is a rare genetic disease caused by mutations in genes related to heme synthesis pathway, Fe-S cluster and mitochondrial protein synthesis. Changes in the SLC25A38 gene have been reported as one of the reasons of non syndromic autosomal recessive congenital sideroblastic anemia. In this study we had two patients in two families with the symptoms of CSA. After performing Whole Exome Sequencing (WES), a novel nonsense variant (c.166C > T, p.Gln56Ter) and a novel frameshift variant (c.220_221insTTCA, p.Leu75HisfsTer79) in the SLC25A38 gene were identified in the families. Then, Sanger sequencing and segregation analysis were used to confirm the variants. The sequencing confirmed that these variants were homozygous in each proband and heterozygous in their parents. After that, the variant effects and its pathogenicity were evaluated using different bioinformatics analysis which identified the existing variant as pathogenic in more cases. The results of real-time PCR also showed that the level of mRNA expression of the gene in the patient with nonsense variant was significantly down-regulated compared to the normal person (p < 0.001). This is one of the first studies about the sideroblastic anemia in Khuzestan province of Iran and its results could indicate the relationship between this gene and CSA in this population. Our findings suggests that the mentioned variants, in an allele of the SLC25A38 gene, by alone, not enough to cause disease. This study also increases the list of mutations involved in the SLC25A38 gene and raises our knowledge about the role of this gene in CSA disease and would be very useful for screening in populations.