GENOTYPE-PHENOTYPE CORRELATIONS IN HEREDITARY SPHEROCYTOSIS: A REVIEW OF COHORT STUDIES

Abstract

Hereditary spherocytosis (HS) is an inherited hemolytic anemia caused by mutations in the ANK1, SPTB, SLC4A1, SPTA1 and EPB42 genes encoding proteins involved in the vertical linkages between the skeletal network and the red blood cell membrane. Despite the accumulation of molecular genetic data, the relationship between genotype and clinical phenotype remains a subject of debate. Aim: To systematize and compare the results of cohort studies investigating genotype-phenotype correlations in HS. Results: ANK1 and SPTB mutations are associated with the most severe phenotype, whereas SLC4A1 mutations more frequently result in a mild phenotype. The severity of SPTA1-HS ranges from the most severe forms to mild and subclinical presentations, determined by the allelic combination, including carriage of the lowexpression αLEPRA/αLELY alleles, and the resulting level of α-spectrin expression. The role of mutation domain localization in predicting disease severity remains controversial. UGT1A1 promoter polymorphism (Gilbert syndrome) serves as an additional modifying factor influencing bilirubin levels and the risk of cholelithiasis. Conclusion: Categorization by the affected gene alone is insufficient for phenotype prediction — the mutation type, its domain localization, and modifier genes must be taken into account.