HBB – Beta-Thalassemia Major

Beta-thalassemia major is a severe autosomal recessive disorder caused by deficient or absent synthesis of the β-globin chain, leading to ineffective erythropoiesis and transfusion-dependent anemia. The HBB gene (HGNC:4827) encodes the β-globin subunit of hemoglobin A, and pathogenic variants result in β⁰ or β⁺ phenotypes depending on the nature of the mutation. Clinically, affected individuals present in early infancy with growth delay, hepatosplenomegaly, jaundice, and hemolytic anemia, requiring lifelong transfusions and chelation therapy.

Genetic evidence for the HBB–beta-thalassemia major association is robust. Multiple case series across diverse populations have identified over 200 unrelated probands (64 in Bulgaria (PMID:2200762); 43 in Taiwan (PMID:8161731); 88 in Pakistan (PMID:37876062)) with biallelic HBB mutations. The inheritance pattern is autosomal recessive, with parents consistently heterozygous carriers. Compound heterozygotes and homozygotes for splice-site, nonsense, frameshift, and large deletion alleles uniformly manifest transfusion-dependent β-thalassemia major.

Segregation studies demonstrate co-segregation of pathogenic alleles with disease in multiple families. In a Northern Thai pedigree, a novel 3.4 kb deletion encompassing HBB was found homozygous in the proband and heterozygous in the mother (PMID:2272839), and in an Afghan kindred a 909 bp deletion segregated with disease in the proband and carrier status in both parents (PMID:20113295). Altogether, at least 19 affected relatives have been documented with clear Mendelian segregation.

The variant spectrum includes canonical splice-site mutations (e.g., c.92+5G>C (PMID:19486366)), nonsense changes (e.g., codon 17 C>A), frameshifts (e.g., c.431del (p.His144LeufsTer?)), and large gene deletions. Recurrent alleles show population specificity; for instance, IVS-I-110 G>A predominates in Mediterranean cohorts, whereas IVS-II-654 C>T is common in southern China.

Functional and experimental evidence supports a loss-of-function mechanism. Mouse models carrying the human IVS-2-654 C>T allele exhibit aberrant splicing and β⁰ thalassemia phenotype analogous to patients (PMID:9490703). In vitro studies of promoter, enhancer, and polyadenylation signal variants demonstrate severely reduced β-globin transcription and processing, leading to α/β chain imbalance.

No credible conflicting evidence has been reported; all studies consistently implicate HBB LoF in β-thalassemia major without alternative gene associations. Prenatal and carrier screening programs worldwide rely on identification of HBB mutations for diagnosis and prevention.

Integration of genetic and functional data confirms a definitive gene‐disease relationship. Molecular testing for HBB variants underpins clinical decision-making, enabling carrier detection, prenatal diagnosis, and targeted therapies such as gene editing. Key Take-home: HBB mutation analysis is essential for accurate diagnosis and management of β-thalassemia major.

References

• Hemoglobin • 1990 • Beta-thalassemia in Bulgaria. PMID:2200762
• International journal of hematology • 1993 • Prenatal and molecular diagnosis of beta-thalassemia major in Taiwan by naturally and amplified created restriction sites. PMID:8161731
• JPMA. The Journal of the Pakistan Medical Association • 2023 • Spectrum Of HBB Gene Variants And Major Endocrine Complications In Thalassemia Patients Of Pakistan. PMID:37876062
• International journal of laboratory hematology • 2010 • Clinical and haematological features in a compound heterozygote (HBB:c.92 + 5G > C/HBB:c.93-2A > C) case of thalassaemia major. PMID:19486366
• Hemoglobin • 2010 • Characterization of a novel deletion causing beta-thalassemia major in an Afghan family. PMID:20113295
• Hemoglobin • 1990 • Beta zero-thalassemia in a Thai family is caused by a 3.4 kb deletion including the entire beta-globin gene. PMID:2272839
• Blood • 1998 • A common human beta globin splicing mutation modeled in mice. PMID:9490703

Evidence Based Scoring (AI generated)