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

Abstract

Introduction: Thalassemias are common monogenic autosomal recessive hemoglobin disorders. The usually asymptomatic heterozygotes (β-thalassemia traits, βTT) may rarely develop non-transfusion-dependent-thalassemia (NTDT) due to co-inheritance of supernumerary α-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 βTT + supernumerary α-globin genes. HBB mutations were tested for by ARMS-PCR and/or Sanger sequencing, ααα^(anti3.7) /ααα^(anti4.2) and deletional α-thalassemia testing by multiplex gap-PCRs, and Xmn1^G γ 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 ± 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 ααα^anti3.7 , while 3 (6.4%) had ααα^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 β-globin mutations. One case showed HBB:c.-138C>T (β⁺⁺ ), while the rest had β⁰ or severe-β⁺ mutations. Symptomatic cases had significantly lower hemoglobins and higher HbF% than asymptomatic ones.

Conclusion: This largest Indian and globally second-largest study reports the βTT + ααα^4.2 state for the first time in such genotypically-complex Indian cases. Supernumerary α-genes should be suspected in all βTT with disproportionate clinical symptoms, mild-to-moderately elevated HbF, and unexplained anisopoikilocytosis.

Keywords: copy number variation; genotyping; hemoglobin disorders; phenotype modifiers; supernumerary α-globin genes; β-Thalassemia.