The molecular genetic spectrum of hereditary spherocytosis in the Russian population

Abstract

Introduction. Hereditary spherocytosis (HS) is a hereditary hemolytic anemia caused by defects in erythrocyte membrane and cytoskeleton due to mutations mainly in five genes: ANK1, SPTB, SPTA1, SLC4A1, and EPB42. The genetic landscape of HS is characterized by considerable interpopulation variability. Aim – to investigate the molecular genetic spectrum of HS in the Russian population. Materials and methods. The study included 240 patients under 21 years of age with genetically confirmed HS. We analyzed the distribution of pathogenic variants by gene, mutation type, frequency of recurrent and previously undescribed variants, and also assessed the genotype–phenotype correlation with disease severity. Results. Pathogenic variants in the SPTB gene were identified in 45.8% of the patients, in the ANK1 gene in 34.6%, in the SLC4A1 gene in 11.3%, and in the SPTA1 gene in 8.3%. In the SPTB and ANK1 genes, loss-of-function mutations, such as nonsense, frameshift, and splice-site mutations, predominated. In the SLC4A1 gene, missense mutations were the most common, whereas in the SPTA1 gene there was a heterogeneous mutation spectrum, including the frequent intronic mutation with low aLEPRA expression. Novel mutations accounted for 54.2% of all variants. In SPTA1-associated HS, complex genotypes were frequently observed: compound heterozygous variants and digenic variants were found in 35% and in 20% of the patients, respectively. Our clinical severity analysis showed that patients with SPTB- and ANK1-associated HS had mostly moderate disease, patients with SLC4A1-associated HS had a mild course with no severe cases, while SPTA1-associated HS was characterized by a relatively high proportion of severe cases. Conclusion. The Russian cohort belongs to populations with an SPTB-dominant mutation pattern and represents one of the largest national cohorts of patients with genetically confirmed HS worldwide.