Clinical significance of mutational variants in beta and alpha genes in patients with hemoglobinopathies from two large greek centres: a complex interplay between genotype and phenotype

Abstract

Abstract Hemoglobinopathies affect patients in the wider Mediterranean area and consist of 4 distinct subgroups: beta thalassemia major (TM), beta thalassemia intermedia (TI), sickle cell disease syndromes (SCD) (homozygous SCD, SCD/beta thalassemia trait) and hemoglobinopathy H (alpha thalassemia). The clinical spectrum of these syndromes varies from mild to severe. Complex interactions between genes and environmental factors form the clinical manifestations in hemoglobinopathies. There is an unmet need to clarify these multifactorial mechanisms. This is the first Greek study, describing mutational alleles (variants in the HBB and HBA1/HBA2 genes, type of mutation and prevalence) in 217 patients with hemoglobinopathies of two large centers in Greece (Larissa and Athens) and associating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). Thus, the complex interplay between corresponding genotypes and phenotypes was investigated. The present study results are in accordance with previous national studies with limited variations, due to regional prevalence of specific gene variants, as expected. The type and prevalence of variants in beta and alpha globin genes differ significantly among countries. In the beta thalassemic or SCD patients of our cohort, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course, whereas the inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype. In cases in whom the genotype and phenotype did not correlate, other factors such as the function or modification of possible regulatory genes or additional nutritional or environmental effects should be investigated.