Abstract
Congenital sideroblastic anemia (CSA) is a rare genetic disorder caused by defects on heme biosynthesis and mitochondrial energy production. This disease is characterized by the presence of ring sideroblasts in the bone marrow caused by excessive iron accumulation in mitochondria of erythroblasts and by anemia of varying severity. In addition to its clinical variability, CSA is also characterized by genetic heterogeneity which required next-generation sequencing technologies to identify responsible gene. In the present study, whole-exome sequencing followed by Sanger sequencing were performed on a consanguineous family including two patients with congenital sideroblastic anemia. Mitochondrial DNA deletion and copy number were tested respectively by long PCR and QPCR. Subsequent bioinformatic investigations were performed using several programs. WES and Sanger sequencing results revealed a novel pathogenic variant c.579-580insT (p.N194X) in the PUS1 gene. Several bioinformatic tools supported that this variant was disease-causing. This variation leads to an incomplete catalytic site which will be probably non-functional and could disturb heme biosynthesis. In addition, no mtDNA deletion was detected in the two patients whereas mtDNA quantification revealed a decrease of mtDNA copy number in P2 and its increasing in P1. The increase in mtDNA copy number, which is most likely connected to a compensatory mechanism, may be the cause of the moderate phenotypic severity observed in P1 with the same p.N194X variant with P2. In conclusion, we identified a novel truncated pathogenic variant in PUS1 gene in two siblings of consanguineous family with intrafamilial phenotypic variability related to mtDNA copy number.