HBA2 – Alpha Thalassemia Spectrum

HBA2 (HGNC:4824) encodes the α2-globin chain essential for hemoglobin tetramer formation; pathogenic variants reduce α-chain output and cause the autosomal recessive alpha thalassemia spectrum (MONDO:0011399). Affected individuals present with microcytic, hypochromic anemia of variable severity depending on the number and type of α-globin genes involved. Heterozygous carriers typically exhibit mild trait, whereas compound heterozygotes or Hb H patients may require transfusions.

1 Clinical Validity

This gene–disease relationship is Definitive. Over decades, >100 different HBA2 variants have been reported in >200 unrelated probands, with consistent autosomal recessive segregation across multiple families and concordant functional data demonstrating α-chain instability and reduced expression.

2 Genetic Evidence

Alpha thalassemia is inherited in an autosomal recessive manner. Segregation in families includes 9 affected relatives in an extended Iranian pedigree (PMID:20670167) and 6 individuals across three generations with Hb Utrecht (PMID:8790146). The variant spectrum comprises deletional alleles (–α3.7, –α4.2, ––SEA), nondeletional point mutations, nonsense, frameshift, and splice-site changes. A representative nonsense mutation is c.70G>T (p.Glu24Ter) observed in a Tunisian family (PMID:15481894). Over 100 HBA2 alleles contribute to >200 diagnosed cases worldwide.

3 Functional Evidence

Mechanistically, loss of functional α2-globin results in α-thalassemia via haploinsufficiency. In vitro studies show that frameshift and nonsense mutations induce premature stop codons leading to nonsense-mediated mRNA decay (e.g., c.69del; PMID:16512835). Protein stability assays confirm that truncated or amino-acid substituted α-chains are degraded rapidly, preventing tetramer assembly and mimicking clinical phenotype.

4 Conflicting Evidence

Large contiguous gene deletions causing ATR-16 syndrome can include HBA2 but present broader developmental delay features (PMID:9375730). Co-inheritance with β-thalassemia or modifier polymorphisms may modulate severity but does not dispute gene–disease validity.

5 Integrated Conclusion

Extensive case series, familial segregation, and functional concordance establish a definitive autosomal recessive association between HBA2 and alpha thalassemia spectrum. Molecular diagnosis of HBA2 variants informs carrier screening, prenatal counseling, and management decisions, with therapeutic interventions tailored to residual α-chain output.

Key Take-home: HBA2 loss-of-function variants cause alpha thalassemia spectrum in an autosomal recessive pattern; genetic and functional testing enables accurate diagnosis and informs clinical management.

References

• British journal of haematology • 2004 • A novel alpha-thalassemia nonsense mutation in codon 23 of the alpha2-globin gene (GAG-->TAG) in a Tunisian family. PMID:15481894
• British journal of haematology • 2006 • Human alpha2-globin nonsense-mediated mRNA decay induced by a novel alpha-thalassaemia frameshift mutation at codon 22. PMID:16512835
• Pediatric hematology and oncology • 2010 • A report of 8 cases with hemoglobin H disease in an Iranian family. PMID:20670167
• British journal of haematology • 1996 • Hb Utrecht [alpha 2 129(H12)Leu-->Pro], a new unstable alpha 2-chain variant associated with a mild alpha-thalassaemic phenotype. PMID:8790146

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