The phenotypic and molecular diversity of hemoglobinopathies in India: A review of 15 years at a referral center

Nadkarni, Anita; Gorakshakar, Ajit; Sawant, Pratibha; Italia, Khushnooma; Upadhye, Dipti; Gorivale, Manju; Mehta, Pallavi; Hariharan, Priya; Ghosh, Kanjaksha; Colah, Roshan

doi:10.1111/ijlh.12948

Cited by 20 publications

(12 citation statements)

References 57 publications

(105 reference statements)

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“…Molecular analysis of the β-globin gene was first carried out to confirm the hemoglobinopathy status in the patient samples by covalent reverse dot blot hybridization (CRDB), amplification refractory mutation system—polymerase chain reaction (AMRS PCR), or by direct DNA sequencing 6 . α-globin gene deletions were detected by multiplex PCR 7 .…”

Section: Methodsmentioning

confidence: 99%

Significance of genetic modifiers of hemoglobinopathies leading towards precision medicine

Hariharan

Gorivale

Sawant

et al. 2021

Sci Rep

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Hemoglobinopathies though a monogenic disorder, show phenotypic variability. Hence, understanding the genetics underlying the heritable sub-phenotypes of hemoglobinopathies, specific to each population, would be prognostically useful and could inform personalized therapeutics. This study aimed to evaluate the role of genetic modifiers leading to higher HbF production with cumulative impact of the modifiers on disease severity. 200 patients (100 β-thalassemia homozygotes, 100 Sickle Cell Anemia), and 50 healthy controls were recruited. Primary screening followed with molecular analysis for confirming the β-hemoglobinopathy was performed. Co-existing α-thalassemia and the polymorphisms located in 3 genetic loci linked to HbF regulation were screened. The most remarkable result was the association of SNPs with clinically relevant phenotypic groups. The γ-globin gene promoter polymorphisms [− 158 C → T, + 25 G → A],BCL11A rs1427407 G → T, − 3 bp HBS1L-MYB rs66650371 and rs9399137 T → C polymorphisms were correlated with higher HbF, in group that has lower disease severity score (P < 0.00001), milder clinical presentation, and a significant delay in the age of the first transfusion. Our study emphasizes the complex genetic interactions underlying the disease phenotype that may be a prognostic marker for predicting the clinical severity and assist in disease management.

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Section: Methodsmentioning

confidence: 99%

Significance of genetic modifiers of hemoglobinopathies leading towards precision medicine

Hariharan

Gorivale

Sawant

et al. 2021

Sci Rep

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“…The carrier frequency has been found to be high in populations where malaria is common [1][2][3]. Cross-national migration from endemic regions has led to spread of the disease [4,5]. Thalassemia is classified into 2 types according to the defective gene: In α-thalassemia, the hemoglobin subunit alpha (HBA) gene cluster is damaged, and in cases of β-thalassemia, there are pathogenic variants in the hemoglobin subunit beta (HBB) gene [6].…”

Section: Association Between Hba Locus Copy Number Gains and Pathogenic Hbb Gene Variantsmentioning

confidence: 99%

Association of HBA gene copy number gains with pathogenic HBB gene variants

Karakaş¹

2021

Int J Med Biochem

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8]. Four alleles of 2 structurally similar genes, HBA1 and HBA2 are responsible for α-globin gene expression and are critically important when establishing genotype-phenotype relationships in patients with β-thalassemia. Although the HBA1 gene Objectives: Alpha (α) and beta (β) thalassemia are the most prevalent genetic hematological disorders. The co-occurrence of silent β-thalassemia with excess α-globin gene copies is associated with the thalassemia intermedia phenotype. This study was an investigation of the α-globulin gene dosage and sequence variations in thalassemia patients. Methods: Multiplex ligation-dependent probe amplification and Sanger sequencing were used to identify the hemoglobin subunit alpha 1 (HBA1) and HBA2 gene alterations in 32 patients. Deletion, duplication, and other findings were analyzed in the index cases and family members. Results: Four of the 32 cases (12.5%) were found to have gross duplications. Two cases demonstrated α-globin triplication, and 2 had a quadruplicated HBA1/2 genes. Affected family members revealed genotype-phenotype correlation. In 1 patient, it was observed that quadruplicated HBA genes co-occurrence with hemoglobin subunit beta (HBB) mutation was inherited from his mother. Notably, the mother did not demonstrate any thalassemia phenotype. Further investigation showed that the mother was carrying a single copy HBA gene deletion in the trans allele that explained her clinical condition. Conclusion:This study examined the effect of increased copies of the HBA gene in HBB gene pathogenic variant carriers. The results indicated that β-thalassemia mutations with a co-occurrence of increased α-globin gene dosage is not very rare condition. Patients with clinical findings incompatible with their HBB genotypes should be investigated for small and gross α-globin gene variants in order to provide genetic counseling and prenatal diagnosis follow-up, as appropriate.

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“…There were a few overlapping cases with other earlier case reports which have not been included here to avoid duplication. Several mutations were reported mainly as compound heterozygotes (Table 1), but the clinical presentation of these cases was not mentioned in the study [20]. Hemoglobin H disease due to homozygous Hb Sallanches was first reported by Dash et al in 2006 in India.…”

Section: Resultsmentioning

confidence: 98%

Molecular Heterogeneity of Hb H Disease in India

Thaker

Mahajan

Mukherjee

et al. 2022

Thalassemia Reports

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Alpha thalassemia is an autosomal recessive disorder caused by large deletions and/or point mutations in the α- globin genes. Hemoglobin H (Hb H) disease is most frequently due to deletion of three of the four α globin genes associated with variable clinical severity depending on the genotype. There are few reports on Hb H disease in Indians where genotyping has been done and we have reviewed the molecular and clinical heterogeneity of these cases. An electronic search for relevant articles was conducted using two journal databases, i.e., PubMed and Science Direct using the key words “Hb H Disease”, “Hemoglobin H”, “α-thalassemia”, “mutations”, “molecular heterogeneity”, “case reports” and “India”. This review was performed based on preferred reporting items for the systematic review and meta-analysis protocols (PRISMA-P) guidelines. The molecular spectrum of Hb H disease in Indians includes the most common [-α3.7, -α4.2, --SA, Poly A (AATAAA→AATA--), Hb Sallanches], rare [--SEA, --MED, IVS 1nt 1 (G→A), Hb Koya Dora, Hb Sun Prairie], very rare [Hb Iberia, Hb Seal Rock, Hb Zürich-Albisrieden] and novel [Codon 76 (+T) and --Kol] α-globin gene mutations inherited largely as compound heterozygotes with considerable clinical variability. The molecular diagnosis of Hb H disease is important for genetic counseling and management.

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The phenotypic and molecular diversity of hemoglobinopathies in India: A review of 15 years at a referral center

Cited by 20 publications

References 57 publications

Significance of genetic modifiers of hemoglobinopathies leading towards precision medicine

Significance of genetic modifiers of hemoglobinopathies leading towards precision medicine

Association of HBA gene copy number gains with pathogenic HBB gene variants

Molecular Heterogeneity of Hb H Disease in India

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