Hematological and genetic profiles of persons with co-inherited heterozygous β-thalassemia and supernumerary α-globin genes

Introduction Thalassemias are common monogenic autosomal recessive hemoglobin disorders. The usually asymptomatic heterozygotes (beta-thalassemia traits, beta TT) may rarely develop non-transfusion-dependent-thalassemia (NTDT) due to co-inheritance of supernumerary alpha-globin genes. Literature on phenotypic/genotypic features of these rare combinations is limited.Materials and Methods We studied the demographic, clinical, and laboratory data from 47 persons with co-inherited beta TT + supernumerary alpha-globin genes. HBB mutations were tested for by ARMS-PCR and/or Sanger sequencing, alpha alpha alpha((anti3.7))/alpha alpha alpha((anti4.2)) and deletional alpha-thalassemia testing by multiplex gap-PCRs, and Xmn1(G)gamma genotyping by PCR-RFLP.Results The 47 cases comprised 0.08% of 61 010 hemoglobinopathy screenings during the study period. Mean age was 31.9 +/- 14.7 years (range 5.5-83 years), with 57.4% males. Thirty (63.8%) had NTDT-phenotype, 16 (34%) were asymptomatic/minimally symptomatic, and 1 became transfusion-dependent at the age of 20 years. Anemia/pallor and jaundice were the commonest complaints (76% each); 40% had required blood transfusions. Twenty-one had splenomegaly, 14 had hepatomegaly. Mean hemoglobin was 9.0 & PLUSMN; 1.9 g/dl (range 4.0-13.0). HbA2 was 5.1 +/- 0.7% (3.4%-6.3%) and HbF% 4.2 +/- 3.2% (0.5%-18.4%). Forty-four (93.6%) had alpha alpha alpha(anti3.7), while 3 (6.4%) had alpha alpha alpha(anti4.2) triplications. HBB:c.92+5G > C (47%), HBB:c.27_28insG (14.9%), and HBB:c.47G > A (8.5%) were the commonest beta-globin mutations. One case showed HBB:c.-138C > T (beta(++)), while the rest had beta(0) or severe-beta(+) mutations. Symptomatic cases had significantly lower hemoglobins and higher HbF% than asymptomatic ones.Conclusion This largest Indian and globally second-largest study reports the beta TT + alpha alpha alpha(4.2) state for the first time in such genotypically-complex Indian cases. Supernumerary alpha-genes should be suspected in all beta TT with disproportionate clinical symptoms, mild-to-moderately elevated HbF, and unexplained anisopoikilocytosis.

Automated summary

This study reports on the rare combination of beta-thalassemia with supernumerary alpha-globin genes. Patients with this combination showed clinical features such as anemia, jaundice, splenomegaly, and hepatomegaly. Symptomatic patients had significantly lower hemoglobin levels and higher fetal hemoglobin levels compared to asymptomatic ones.