X-linked sideroblastic anaemia associated with beta thalassemia trait presenting with a peculiar chronic anaemia phenotype in a 47-years-old woman

Background: Chronic anaemias represent a clinical challenge and are frequently associated with a prolonged diagnostic odyssey. We present the case of a 47-year-old woman affected by progressive severe anaemia and progressive splenomegaly since the age of 30. She was initially diagnosed with intermediate thalassemia due to an imbalance in alfa/beta globin chain synthesis (1.83), although only a single beta-globin gene mutation (HBB: c.93-21G>A) was identified. The serious clinical evolution was not consistent with the molecular data and further investigations were considered mandatory. Materials and methods: Whole Genome Sequencing (WGS) was performed in the hypothesis of a germinal or somatic polygenic molecular pathogenesis Results: WGS revealed the c.1273C>A (p.Pro425Thr) maternally inherited pathogenic variant in the ALAS2 gene. Complete opposite skewed X inactivation has been observed in the blood of the proband and her healthy mother, explaining the observed contrasting phenotypes. A bone marrow biopsy confirmed the diagnosis showing the presence of 31% ringed sideroblasts in the proband. The ALAS2 variant is located within the dimerization interface region of the protein, likely impairing dimer stability and enzymatic activity, mapping in the proximity to the Vitamin B6 (VB6) binding site. Administration of high doses of VB6, an approved therapy for X-linked sideroblastic anaemia, has been attempted without any clinical benefit and the patient currently undergoes recurrent blood transfusions. Conclusion: Complex acquired clinical phenotype, such as chronic anaemias, can be adequately diagnosed with comprehensive genomic analysis as they may pave the way for personalized treatment strategies, improved follow-up strategies and specific therapeutic options.