HBA2 – Hemoglobin H Disease

Hemoglobin H (HbH) disease is an autosomal recessive α-thalassemia characterized by β₄ tetramer formation due to insufficient α-globin chains. HBA2 (HGNC:4824) loss‐of‐function and missense mutations in trans with common α-thalassemia deletions or other HBA2 alleles underlie the clinical phenotype of moderate microcytic hypochromic anemia with HbH inclusion bodies ([PMID:8555062]).

Genetic evidence includes at least eight unrelated probands: one homozygous for HBA2:c.314G>A (p.Cys105Tyr) ([PMID:8555062]), one de novo frameshift mutation compounded with –SEA deletion ([PMID:20691621]), one compound heterozygote HBA2:c.377T>C (p.Leu126Pro) with –SEA ([PMID:39207010]), one –SEA/–α2.8 deletion compound heterozygote ([PMID:23289204]), and five patients carrying HBA2:c.95G>A (p.Arg32Lys) in trans with various α-thalassemia deletions ([PMID:39501461]). No multi‐generational segregation beyond probands has been reported.

The variant spectrum in HbH disease comprises non-deletional missense alleles (e.g., c.314G>A, c.377T>C, c.95G>A) and frameshift/deletion alleles. Recurrent Southeast Asian –SEA and –α3.7 deletions are common in trans configuration. Carrier frequency of HBA2:c.95G>A in heterozygotes is observed in Asian populations, where combination with –SEA yields HbH disease ([PMID:39501461]).

Functional studies demonstrate that missense variants and splice defects reduce α2-globin mRNA stability or protein synthesis. In vitro erythroid expression of HBA2:c.314G>A shows unstable α Sal:β dimers ([PMID:8555062]), while expression of HBA2:c.329T>G (p.Leu110Arg) and splice‐site mutations confirm decreased transcript or protein levels consistent with thalassemic phenotypes ([PMID:2265255], [PMID:21967524]).

The mechanism of pathogenicity in HbH disease is predominantly due to quantitative α-globin deficiency (haploinsufficiency), leading to excess β-chain tetramers. Experimental models recapitulate the human phenotype with reduced α-chain synthesis and destabilized tetramers.

No studies have directly refuted the association between HBA2 coding mutations and HbH disease. Additional evidence from large cohorts and animal models exists but exceeds the scope of current scoring.

Key Take-home: HBA2 coding mutations in trans with common α-thalassemia deletions reliably cause HbH disease, supporting targeted molecular diagnosis and carrier screening in at‐risk populations.

References

• British journal of haematology • 1995 • A new alpha chain variant Hb Sallanches [alpha 2 104(G11) Cys-->Tyr] associated with HbH disease in one homozygous patient. PMID:8555062
• Blood cells, molecules & diseases • 2010 • Hemoglobin H disease due to a de novo mutation at the α2-globin gene and an inherited common α-thalassemia deletion found in a Chinese bo PMID:20691621
• The Malaysian journal of pathology • 2024 • A rare case of compound heterozygous Southeast Asian double α-globin gene deletion and Haemoglobin Quong Sze in a Malay proband PMID:39207010
• Clinical laboratory • 2012 • A novel deletion of -2.8 kb removing the entire alpha 2-globin gene observed in a Chinese patient with Hb H. PMID:23289204
• Hemoglobin • 2024 • Phenotypic Analysis of the HBA2: C.95 > A Mutation in Chin PMID:39501461

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