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

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 rst 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 speci c gene variants, as expected. The type and prevalence of variants in beta and alpha globin genes differ signi cantly 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 modi cation of possible regulatory genes or additional nutritional or environmental effects should be investigated. Key MessageThis is the rst Greek study, fully molecularly de ning the beta and alpha mutational alleles in 217 patients with hemoglobinopathies of two large centers in Greece Particular genotypes or gene variants were associated with clinical manifestations (transfusion frequency, complications)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 The inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype The function or modi cation of possible regulatory genes should be investigated in cases in whom the genotype and phenotype did not correlate

Measurement of erythrocyte lifespan using a CO breath test in patients with thalassemia and the impact of treatment

“…In patients with β-thalassemia, co-inheritance of α-globin gene variants, leading to absence or reduction of α-globin synthesis, were associated with a milder clinical course. 18 In our cohort, ELS was significantly higher in patients with Mix and significantly higher than that in patients with TI, which further confirmed that co-inheritance of α-thalassemia alleviated hemolysis in patients with β-thalassemia. However, the CO concentration and ELS in patients with Mix were more similar to those in patients with TM.…”

Alpha globin gene alterations modifying the phenotype of homozygous beta thalassaemia

“…They concluded that co‐inheritance of α−3.7 among 15 TM increased haemoglobin level reduced severity whereas double heterozygotes with α‐triplication and TI presented with a more severe phenotype. However, no frequency or rate was mentioned in the study [ 19 ].…”

“…[ 23 ] found α‐triplication in three β thal patients having β 0 /β + or β ++ and 26 β thal carriers but having severe clinical presentation out of 181 patients studied, whereas Farashi et al. [ 19 ] found α‐triplication in 14 β thal carriers and 9 β‐thal major out of 1700 patients studied. None of them commented on the influence of α‐triplication on disease severity.…”

“…. Mehta et al[23] found α-triplication in three β thal patients having β 0 /β + or β ++ and 26 β thal carriers but having severe clinical presentation out of 181 patients studied, whereas Farashi et al[19] found α-…”