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 β 0 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.