Hematological and genetic profiles of persons with co‐inherited heterozygous β‐thalassemia and supernumerary α‐globin genes. (14th January 2023)

• Record Type: Journal Article
• Authors: Sundaresan, Durga Devi; Hira, Jasbir Kaur; Chhabra, Sanjeev; Trehan, Amita; Khadwal, Alka Rani; Malhotra, Pankaj; Sharma, Prashant; Das, Reena
• Is Part Of: European journal of haematology. Volume 110:Number 5(2023)
• Page Start: 510
• Page End: 517
• Publication Date: 2023-01-14
• Subjects: copy number variation -- genotyping -- hemoglobin disorders -- phenotype modifiers -- supernumerary α‐globin genes -- β‐Thalassemia; Hematology -- Periodicals; Blood -- Diseases -- Periodicals; Blood -- Periodicals; 616.15005
• DOI: 10.1111/ejh.13923
• Languages: English
• ISSNs: 0902-4441

Abstract

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.