HBB – Dominant Beta-Thalassemia

HBB, encoding the beta-globin subunit, is associated with autosomal dominant beta-thalassemia, a semi-dominant hemoglobinopathy characterized by microcytic anemia, jaundice, cholelithiasis, and splenomegaly. Pathogenic HBB variants produce unstable beta chains that drive chronic hemolysis via haploinsufficiency and/or dominant-negative effects, necessitating early genetic diagnosis for optimal management.

Two unrelated case reports identified pathogenic HBB variants: c.347C>A (p.Ala116Asp) in a mother–daughter pair with hemoglobin Hradec Kralove (2 probands; [PMID:14686490]) and an 11-base-pair deletion c.394_404del (p.Gln132fs) in a 51-year-old male with inclusion body beta-thalassemia (1 proband; [PMID:15977037]). Both variants lead to aberrant beta-chain synthesis and a dominant thalassemia phenotype.

A multicenter NGS series in five unrelated patients with chronic hemolytic anemia uncovered four additional HBB variants—including c.290T>C (p.Leu97Pro) and c.202G>A (p.Val68Met)—all correlating with dominant beta-thalassemia (5 probands; [PMID:33613322]). This expands the allelic heterogeneity and confirms recurrence across diverse ethnicities.

Segregation analysis is demonstrated by co-segregation of c.347C>A (p.Ala116Asp) in a mother and daughter (1 additional affected relative; [PMID:14686490]), supporting an autosomal dominant inheritance pattern.

Functional studies in patient erythrocytes show increased osmotic fragility on saline and coiled-planet centrifugation, prolonged glycerol lysis time, and weakly positive isopropanol tests, consistent with variant-induced membrane instability and enhanced hemolysis ([PMID:14686490]).

Clinically, splenectomy was effective in ameliorating hemolysis in 5 of 7 patients with codon 115 variants (Hb Madrid and Hb HK), highlighting the utility of genotype-driven therapeutic decisions ([PMID:14686490]).

Taken together, genetic and experimental data support a Moderate ClinGen classification for HBB–dominant beta-thalassemia, with concordant functional assays and multi-familial observations. Early molecular testing enables precise diagnosis, prognostication, and timely intervention.

References

• International journal of hematology • 2003 • Dominant beta-thalassemia with hemoglobin Hradec Kralove: enhanced hemolysis in the spleen. PMID:14686490
• Annals of hematology • 2005 • A deletion of 11 bp (CD 131-134) in exon 3 of the beta-globin gene produces the phenotype of inclusion body beta-thalassemia. PMID:15977037
• Frontiers in physiology • 2021 • Usefulness of NGS for Diagnosis of Dominant Beta-Thalassemia and Unstable Hemoglobinopathies in Five Clinical Cases. PMID:33613322

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