HBB – Beta Thalassemia

Beta thalassemia is an autosomal recessive hemoglobinopathy caused by reduced or absent synthesis of the β-globin chain encoded by HBB (HGNC:4827). Clinically it ranges from asymptomatic carrier states to transfusion-dependent intermedia and major phenotypes characterised by microcytic hypochromic anemia, splenomegaly and iron overload.

Clinical Validity

AR inheritance is established with segregation in numerous pedigrees, including a Swedish family of seven heterozygotes across three generations (PMID:7864023). In a cohort of Thai patients, 116 distinct β-thalassemia alleles were identified among 78 Hb E/β-thalassemia patients and 19 homozygous β-thalassemia probands (PMID:2393018), with 97% mutation detection. Extensive functional concordance supports a Definitive gene–disease association.

Genetic Evidence

HBB variants act via haploinsufficiency. Over 200 unique mutations have been described: nonsense (e.g., c.108C>A (p.Tyr36Ter)), splice-site (c.316-1G>C), promoter (–87 C>T) and 3′UTR (c.*111A>G) changes (PMID:8112743). Recurrent alleles such as IVS-I-110 (c.93-21G>A) and codon 39 (c.116C>T) account for high population frequencies, enabling targeted screening in Mediterranean, Southeast Asian and Middle Eastern groups.

Functional Evidence

Promoter mutations in the proximal CACCC box (–87 C>T) reduce transcription to 45–51% (PMID:2018842). Polyadenylation signal alterations (AATAAA→AATGAA) yield extended transcripts of 1.5–2.9 kb (PMID:1374896). The common IVS-2-654 C→T splicing mutation has been modeled in mice, reproducing aberrant β-globin processing and severe anemia (PMID:9490703).

Experimental Concordance

An in vitro MEL cell system recapitulates mutant β-globin expression, showing aberrant splicing and mRNA instability for both IVS-2-654 and 5′ UTR mutations (PMID:10519995). These cellular assays confirm the loss-of-function mechanism and allow evaluation of potential splice-correcting therapies.

Clinical Utility & Take-Home

Routine molecular testing of HBB enables precise carrier detection, prenatal diagnosis and PGD. Knowledge of specific HBB mutations informs transfusion planning, iron chelation and potential curative approaches (bone marrow transplant or gene therapy).

Key Take-home: Definitive evidence establishes HBB haploinsufficiency as the mechanism of autosomal recessive β-thalassemia, underpinning robust genetic testing and therapeutic decision-making.

References

• American Journal of Human Genetics • 1990 • The molecular basis of beta-thalassemia in Thailand: application to prenatal diagnosis. PMID:2393018
• American Journal of Hematology • 1995 • Initiation codon mutation (ATG → ATA) of the beta-globin gene causing beta-thalassemia in a Swedish family. PMID:7864023
• Blood • 1990 • Sickle cell anemia, sickle cell beta-thalassemia, and thalassemia major in Albania: characterization of mutations. PMID:8112743
• Proceedings of the National Academy of Sciences of the United States of America • 1992 • Two mutations in the beta-globin polyadenylylation signal reveal extended transcripts and new RNA polyadenylylation sites. PMID:1374896
• Blood • 1998 • A common human beta globin splicing mutation modeled in mice. PMID:9490703
• British Journal of Haematology • 1999 • An in vitro system for expression analysis of mutations of the beta-globin gene: validation and application to two mutations in the 5′ UTR. PMID:10519995
• Blood • 1991 • Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element. PMID:2018842

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