Genotype-phenotype correlation in alpha-thalassemia: predicting genetic subgroups via laboratory parameters

Alpha-thalassemia is caused by deletional and/or mutational genetic abnormalities. Limited information exists in Saudi Arabia about the genotype-phenotype correlation. We asked if certain changes in laboratory parameters can predict the underlying genetic subgroup.

All patients diagnosed with genetically defined alpha-thalassemia at King Saud University Medical City between 2017 and 2024 were included. Data were collected retrospectively. We hypothesized that there is no difference between the mutation and deletion groups in terms of complete blood count, hemoglobin electrophoresis parameters, or ferritin. Mann-Whitney U and independent samples t-tests were used for between-group comparisons. Fisher's exact or chi-square tests were used for categorical variables. Two-sided p-values of <0.05 were considered statistically significant. A descriptive summary was conducted for all the other variables.

A total of 378 patients were identified with alpha-thalassemia, of whom 276 had deletion, 64 had mutation, and 38 had both mutation and deletion. Of the 340 patients included in the final comparative analysis, the median age was 27 years, and 216 were female. Higher indirect bilirubin (12.3% versus 4%, p-value 0.013), mean red cell distribution width (RDW) (18.8 versus 17.1, p-value of 0.005), and heterozygous genotype status (71.9% versus 57.5%, p-value 0.036) were seen in the mutation group. Hemoglobin H (HbH) detectability was higher in the mutation group than in the deletion group (1.63 versus 0.02, p-value <0.001). These differences in RDW % and HbH detectability held true even after adjusting for sickle hemoglobin (HbS) level, with p-values of 0.006 and <0.001, respectively. No statistical difference was found between the two groups in ferritin level.

Alpha-thalassemia mutations create a distinct hematologic phenotype characterized by increased red cell size variability, indirect bilirubin, and HbH compared to deletions, supporting different pathophysiological mechanisms. These could serve as simple laboratory markers to help distinguish between alpha-thalassemia subtypes, supporting the hypothesis that mutations create a more severe hemolytic phenotype than deletions.