Pb2237: hematimetric detection of the triplication of alpha-globin genes. the importance of your diagnosis

Background: The triplication of alpha-globin genes (ααα) caused by homologous recombination between duplicated alpha-globin genes, rarely presents with detectable clinical symptoms since hematometric parameters appear normal. There are two types of α-globin gene triplication, αααanti3.7 and αααanti4.2. αααanti4.2is very common among Asians, whereas αααanti3.7 is more common in African, Middle Eastern, and Mediterranean populations. The number of α genes plays a very important role in the thalassemia phenotype. The co-heritability of a triplication of alpha genes (αααanti3.7) is considered an important factor in the severity of β-thalassemia, exacerbating its phenotypic expression, by causing more imbalance between globin chains, behaving like a β -thalassemia intermedia that in some cases require regular transfusions. Thus, detection of αααanti3.7 carriers would be of great help in preventing severe cases of thalassemia. Aims: Triplications are considered rare because the de novo crossover events that generate them occur infrequently. In our laboratory, approximately 85% of the alterations in the alpha globin chain are due to large deletions, the most frequent being -α3.7. However, reviewing the results of the alterations in the alpha genes in our laboratory, we have observed that triplications are not as infrequent as previously thought, either alone or associated with β-thalassemia. To this end, we consider hematometric characterization of the heterozygous alpha gene triplication (αααanti3.7). Methods: Retrospective case/control study from 2013 to 2020. Fifty healthy controls and 48 cases were carriers of the alpha gene triplication (αααanti3.7) in the heterozygous state. Hematological parameters and reticulocyte count were determined on a Coulter LH750 analyzer. Hb A2 and Hb F levels were measured by ion-exchange HPLC (VARIANTTM). Patients with elevated Hb A2 compatible with β-thalassemia or increased Hb F were discarded. Only were selected the subjects did not present abnormal hemoglobins by zonal capillary electrophoresis and ion exchange HPLC. Molecular characterization was carried out by multiplex PCR with the commercial Alpha-Globin StripAssay kit and confirmed by MLPA (SALSA Probemix P140 HBA). Results: A total of 7625 samples have been analyzed in 8 complete years and a total of 121 triplications have been identified, 73 associated with β-thalassemia, the rest 48 alone. The incidence was 1.58% and taking into account that the incidence of α-thalassemia in Spain is 4.79%, it is one-third of the incidence of α-thalassemia. The hematological data appear collected in the table. Image:Summary/Conclusion: The heritability of an alpha gene triplication is in many cases underdiagnosed as it does not present clinical complications. This study shows that the α-globin gene triplication presents Hb levels, MCV, MCH, and MCHC decreased concerning controls, with Hb A2 levels close to 3%. Although there is an overlap of the red blood cell indices at the low limit of normality, a triplication of alpha genes should be suspected, especially when HbA2 levels are at the high limit of normality. Above all, in cases where genetic counseling is requested because the partner has heterozygous β-thalassemia and the transmission of both alterations would aggravate the clinical picture.