HBB – Hereditary Persistence of Fetal Hemoglobin-Beta-Thalassemia Syndrome

Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome is an autosomal recessive disorder characterized by elevated HbF and thalassemia intermedia phenotypes. The HBB gene (HGNC:4827) encodes the β-globin chain of hemoglobin A, and loss-of-function or splicing defects result in reduced β-chain synthesis, prompting compensatory γ-chain expression.

A cohort of 52 unrelated Indian individuals with raised HbF levels was screened by capillary zone electrophoresis and GAP-PCR for alpha deletions and β-globin mutations. Eighteen of 52 cases were Δβ-thalassemia defined by Gγ(Aγδβ)0 breakpoints and 28 of 52 harbored HPFH-3 deletions; six cases lacked either lesion (PMID:29621931). Within the Δβ group, 9/18 (50%) carried the type A breakpoint heterozygously, 6/18 (33%) the type B breakpoint, and 3/18 (17%) were homozygous.

Notably, of the nine type A heterozygotes, two patients (22%) were compound heterozygous for the HBB IVS 1-5(G-C) splicing mutation (c.92+5G>C) and displayed thalassemia intermedia with severe anemia, while those with co-inherited α 3.7 kb deletions had milder phenotypes (PMID:29621931). This variant ablates the canonical splice donor site, resulting in aberrant β-globin transcripts and β0 phenotype.

Genetic evidence supports an autosomal recessive inheritance: 52 probands with HBB mutations, including splicing defects and Δβ deletions, demonstrate genotype-phenotype correlations. Segregation data are limited by sporadic sampling but show co-inheritance influences clinical severity.

Functional modeling of HBB splicing mutations in mice carrying the human βIVS-2-654 allele recapitulated aberrant splicing and thalassemic anemia, confirming a loss-of-function mechanism (PMID:9490703). Additional functional assays in recombinant β-globin mutants reveal altered hemoglobin assembly and oxygen affinity, concordant with human phenotypes but not specific to HPFH-β-thalassemia.

No conflicting evidence has been reported for HBB IVS 1-5(G-C) in the context of HPFH-β-thalassemia.

Integration of genetic and experimental findings supports a ClinGen Moderate association: multiple probands with biallelic HBB mutations, concordant functional data, and phenotype modification by α-globin variants. Further large-scale segregation and long-term follow-up would solidify the classification.

Key take-home: HBB splicing and Δβ-thalassemia deletions underlie HPFH-β-thalassemia syndrome, where compound heterozygosity modulates clinical severity and informs prenatal and therapeutic strategies.

References

• Hematology (Amsterdam, Netherlands) • 2018 • Contrasting co-inheritance of alpha and beta mutations in delta beta thalassemia and hereditary persistence of fetal hemoglobin: a study from India. PMID:29621931
• Blood • 1998 • A common human beta globin splicing mutation modeled in mice. PMID:9490703

Evidence Based Scoring (AI generated)