Prevalence of Alpha-Globin Gene Deletions amongst Patients with Unexplained Microcytosis in a North-American Population.

Abstract Introduction: Increasing multi-ethnicity is likely to make α-thalassemia more prevalent in western metropolitan areas. The current prevalence of α-thalassemia in regions outside the traditional thalassemia areas with the associated risk for HbH disease and hydrops foetalis is unknown. Genetic counseling for reproductive risks due to α-globin gene mutations requires adequate and precise genotyping. Objectives: To determine by multiplex polymerase chain reaction (m-PCR) the prevalence and genotypes of α-thalassemia among non selected, consecutive cases of unexplained microcytosis identified in a clinical hematology laboratory. To evaluate if differences or variations in erythrocytic indices are indicative of α-thalassemia. Methods: During a period of 3 months, α-globin genotype was determined by m-PCR on all non repetitive microcytic (MCV <80fL) blood samples from adults with normal ferritin and normal hemoglobin HPLC analysis (Variant I, Bio-Rad). A previously described m-PCR analysis allowed the detection of α-globin gene deletions and specifically identified each of the following 7 deletions when present: −α3.7, −α4.2, −−SEA, −−FIL, −−MED, −−THAI and −α(20.5). Results: 516 microcytic blood samples were evaluated of which 197 had normal ferritin and Hb HPLC analysis and were submitted for m-PCR. Among 196 interpretable m-PCRs, 148 did not have α-globin gene deletion(s) (group 1) and 48 α-thalassemia cases (24,5%) were identified: 28 cases of single α-globin gene deletion (group 2) and 20 cases of 2 α-globin gene deletions (group 3). In group 3, 6 cases showed deletions in cis. Results on differences between the groups are presented in Table 1. Even though some differences were statistically different, none was clinically useful and diagnostic. Conclusion: A significant proportion (24,5%) of cases with microcytosis not likely explained by iron deficiency, inflammation or a hemoglobinopathy are caused by α-globin gene deletion(s). This laboratory survey, despite a short period of sample collection (3 months) identified 6 carriers of a 2 gene deletion in cis that may have a severe impact on reproductive decisions and potential future utilisation of resources. These findings are likely to be reproducible in other North American cosmopolitan cities where α-thalassemia is not endemic but likely to be of increasing prevalence due to immigration. The availability, precision and reliability of diagnostic methods such as m-PCR and the increasing ethnic diversity of North-American cities point to an emerging need to develop genetic counseling programs based on the molecular diagnosis of α-thalassemia. Erythrocytic parameters with their standard deviation in the different α-globin genotype groups RBC (x1012/L) MCH (pg) Hb (g/dL) Mentzer† RDW MCV (fL) † calculated for samples with Hb>90 g/L *indicates values that are significantly different from data of other groups. RBC: Red Blood Cells, MCH: Mean Corpuscular Hemoglobin, Hb: Hemoglobin, RDW: Red Cells Distribution Width, MCV: Mean Corpuscular Volume group 1 (normal genotype) 4,27±0,75 * 25±1,5 107±20 * 17,4±2,4 * 17,0±3,1 * 76,6±3,2 group 2 (single α-globin gene deletion) 4,70±0,85 25,2±1,5 118±22 16,2±2,9 * 15,1±2,1 76,9±3,5 group 3 (double α-globin gene deletion) 5,20±0,57 23,2±1,3 * 120±9 14,1±2,1 * 14,8±2,8 72,4±3,0 *

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