The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity

Abstract

Background: The clinical syndrome of thalassemia intermedia (TI) results from the beta-globin genotypes in combination with factors to produce fetal haemoglobin (HbF) and/or co-inheritance of alpha-thalassemia. However, very little is currently known of the molecular basis of Chinese TI patients.

Methods: We systematically analyzed and characterized beta-globin genotypes, alpha-thalassemia determinants, and known primary genetic modifiers linked to the production of HbF and the aggravation of alpha/beta imbalance in 117 Chinese TI patients. Genotype-phenotype correlations were analyzed based on retrospective clinical observations.

Results: A total of 117 TI patients were divided into two major groups, namely heterozygous beta-thalassemia (n = 20) in which 14 were characterized as having a mild TI with the Hb levels of 68-95 g/L except for five co-inherited alphaalphaalphaanti-3.7 triplication and one carried a dominant mutation; and beta-thalassemia homozygotes or compound heterozygotes for beta-thalassemia and other beta-globin defects in which the beta+-thalassemia mutation was the most common (49/97), hemoglobin E (HbE) variants was second (27/97), and deletional hereditary persistence of fetal hemoglobin (HPFH) or deltabeta-thalassemia was third (11/97). Two novel mutations, Term CD+32(A-->C) and Cap+39(C-->T), have been detected.

Conclusions: Chinese TI patients showed considerable heterogeneity, both phenotypically and genotypically. The clinical outcomes of our TI patients were mostly explained by the genotypes linked to the beta- and alpha-globin gene cluster. However, for a group of 14 patients (13 beta0/betaN and 1 beta+/betaN) with known heterozygous mutations of beta-thalassemia and three with homozygous beta-thalassemia (beta0/beta0), the existence of other causative genetic determinants is remaining to be molecularly defined.

Figure 1

Identification of two novel mutations showing the (A)Term CD+32(A-C) and the (B) Cap+39(C-T). The hematological data and α/β globin genotype of two family members are listed in tables. The probands are labeled by the arrow in the family pedigrees. DNA sequences of sense strand are also shown, downward arrows indicating the mutation nucleotides (overlapping peaks are indicated by N). The alignment of β-globin sequences are shown on the bottom. (EMBL accession No.: chimpanzee ENSPTRT00000006177, human ENST00000335295, horse ENSECAT00000010442, monkey ENSMMUT00000006876, mouse ENSMUST00000098192, and zebrafish ENSDART00000101713). *(Blood samples not avaiable). T+32: Term CD+32(A-C), 27-28:CD 27-28(+C), +39:Cap+39(C-T), and 41-42: CD 41-42 (-CTTT).