Molecular basis of a high Hb A/Hb F-thalassemia trait: a retrospective analysis, genotype-phenotype interaction, diagnostic implication, and identification of a novel interaction with -globin gene triplication.

Background: -thalassemia deletion removing 5´-globin promoter usually presents phenotype with high hemoglobin (Hb) A and Hb F levels. We report the molecular characteristics and phenotype-genotype correlation in a large cohort of the -thalassemia with 3.4 kb deletion.

Methods: A total of 148 subjects, including 127 heterozygotes, 20 Hb E--thalassemia patients, and a double heterozygote with -globin gene triplication, were recruited. Hb and DNA analysis were performed to identify thalassemia mutations and four high Hb F single nucleotide polymorphisms (SNPs) including four base pair deletion (-AGCA) at -globin promoter, rs5006884 on OR51B6 gene, -158 -I, BCL11A binding motifs (TGGTCA) between 3´ -globin gene and 5´-globin gene.

Results: It was found that heterozygous -thalassemia and Hb E- -thalassemia with 3.4 kb deletion had significantly higher Hb, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and Hb values as compared with those with other mutations. Co-inheritance of heterozygous -thalassemia with 3.4 kb deletion and -thalassemia was associated with even higher MCV and MCH values. The Hb E- -thalassemia patients carried a non-transfusion-dependent thalassemia phenotype with an average Hb of around 10 g/dL without blood transfusion. A hitherto undescribed double heterozygous -thalassemia with 3.4 kb deletion and -globin gene triplication presented as a plain -thalassemia trait. Most of the subjects had wild-type sequences for the four high Hb F SNPs examined. No significant difference in Hb F was observed between those of subjects with and without these SNPs. Removal of the 5´-globin promoter may likely be responsible for this unusual phenotype.

Conclusions: The results indicate that -thalassemia with 3.4 kb deletion is a mild -thalassemia allele. This information should be provided at genetic counseling and prenatal thalassemia diagnosis.