Genotype-to-phenotype correlations in hereditary spherocytosis

Abstract

The heterogenous nature of hereditary spherocytosis (HS), both genetically and regarding clinical expression, complicates the prediction of disease severity on an individual level. In this retrospective cohort study collected data used for diagnostics of 197 HS patients referred to University Medical Centre Utrecht (UMCU, the Netherlands) was used to study genotype-to-phenotype correlations in HS. From the included haematological parameters, Laser assisted Optical Rotational Cell Analyzer (LoRRca MaxSis) Osmoscan profiles and other diagnostic tests, the parameters red blood cell distribution width (RDW; r= 0.692, P= 0.000), maximal elongation index (EImax; r=-0.559, P= 0.000) and eosin-5’-maleimide assay (EMA; r=-0.433, P= 0.000) appeared to be the best predictors of clinical severity, respectively. Genetic analysis has identified a causative genetic defect for 185/197 (93.3%) of the patients included. With disease severity classified according to Eber’s classification system (1990), no direct relationship between genotype and clinical severity could be detected (χ2, P= 0.054). Nevertheless, both haematological parameters and Osmoscan parameters -correlated to disease severity though not included in this classification system- imply that SPTB-HS patients have a predominantly more severe clinical picture and SLC4A1-HS patients are generally less severely affected. Apart from the exploration of genotype-to-phenotype correlations in this cohort, a side study was performed on the carriers of Low Expression alleles Lyon (αLELY) and PRAgue (αLEPRA) to gain insight on the pathogenicity and inheritance patterns of these alleles. Finally, a first step has been taken in characterizing the subpopulation of HS patients showing distinctively different, non-classical, Osmoscan profiles identifiable by an increased Ohyper, and here defined as overhydrated HS.