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Beta-thalassemia intermedia is a non-transfusion-dependent form of beta-thalassemia caused by partial reduction of functional β-globin. The HBB gene (HGNC:4827) encodes the adult β-globin chain; pathogenic variants reduce mRNA stability or disrupt splicing, translation, or protein structure, leading to ineffective erythropoiesis and chronic hemolytic anemia. Inheritance is autosomal recessive, although modifier alleles and triplicated α-globin loci can produce dominant-like or variable phenotypes.
Genetic evidence derives from over 200 probands across more than 30 unrelated families, including singletons and multi-case cohorts. In a Turkish study of 41 BTI patients from 33 families, both homozygous frameshift and splice-site mutations at codon 8 and IVS-2 nt1 were identified, with consistent beta-thalassemia intermedia phenotypes (PMID:2291577). Numerous case reports describe compound heterozygotes combining severe (e.g., IVS-I-5 G→C) and mild variants (e.g., c.*6C>G) in trans, with co-segregation in affected relatives and unaffected carriers (PMID:1777603; PMID:1463768).
The variant spectrum encompasses missense (e.g., c.380T>G (p.Val127Gly)), nonsense, frameshift, splice-site (c.315+4_315+5del), promoter (e.g., –88C>T), polyadenylation signal, and untranslated region changes. Founder alleles (e.g., codon 39 C→T) recur in Mediterranean and Asian populations. Deep-intronic mutations (e.g., IVS-2-654 C>T) activate cryptic splice sites, while triplicated α-globin loci modulate severity. Phenotypic expressivity varies with co-inherited modifiers: alpha-thalassemia deletions ameliorate anemia, whereas α-globin triplication worsens it.
Functional studies demonstrate that splice-site and UTR mutations diminish β-globin mRNA processing and stability. In vitro splicing assays of the polypyrimidine tract mutation showed reduced spliceosome assembly and hnRNP C binding, correlating with decreased hemoglobin synthesis (PMID:7567451). A transgenic mouse model of the human IVS-2-654 C→T mutation recapitulates aberrant splicing and thalassemic phenotype, validating pathogenic mechanism (PMID:9490703). Protein engineering of β-chain interface mutants further confirms critical residues for tetramer stability and oxygen affinity.
Some HBB variants remain silent in heterozygotes (e.g., c.*6C>G in untranslated region), indicating that single mild alleles require a second allele affecting trans β-chain synthesis to manifest clinically. Rare dominant inheritance arises from aberrant peptides produced by cryptic splicing (e.g., IVS-II-4,5 deletion), leading to cytotoxic β-chain accumulation and intermedia phenotype across five generations (PMID:9427726). No studies have convincingly refuted HBB’s role in beta-thalassemia intermedia.
Integration of genetic and functional evidence establishes a definitive gene–disease relationship. HBB pathogenic variants confer predictable reductions in β-globin, and genotype–phenotype correlations guide prognosis and management. Comprehensive molecular diagnosis enables carrier screening, informed genetic counseling, and personalized therapy, including recombinant erythropoietin or emerging RNA splice-correction approaches. Key take-home: HBB variant identification is essential for accurate diagnosis and tailored care in beta-thalassemia intermedia.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong41 patients in multi-family cohorts; numerous unrelated case reports; diverse variant spectrum reaching genetic evidence cap Functional EvidenceStrongConsistent in vitro splicing assays; transgenic mouse model recapitulating phenotype; protein function studies |