HBB – Delta-Beta Thalassemia

Delta-beta thalassemia is an autosomal recessive hemoglobinopathy caused by large deletions in the HBB gene cluster that abrogate both delta (HBD) and beta (HBB) globin chain synthesis, resulting in elevated fetal hemoglobin (HbF) levels and mild anemia. The HBB gene (HBB) is definitively implicated through case reports and multi-patient studies in the reduction of delta and beta synthesis consistent with MONDO_0016489 (Delta-Beta Thalassemia).

1. Clinical Validity

The association is classified as Moderate based on five probands across three unrelated families with confirmed large deletions and concordant hematological and molecular data. A heterozygous father and his two daughters presented with elevated HbF (~20%) and microcytic indices, consistent with delta-beta trait ([PMID:27134860]). A separate homozygous case exhibited severe HbF elevation (89.5%) and chronic hemolytic anemia ([PMID:39640193]) and two unrelated families were confirmed by LC-MS/MS and MLPA ([PMID:38212249]).

2. Genetic Evidence

Mode of inheritance: Autosomal recessive. Segregation: 2 additional affected relatives with heterozygous deletions. Case series: five probands harboring large deletions spanning HBD and HBB with absent delta and beta chain production. Variant spectrum: multi-kilobase deletions identified by MLPA; no point mutations described. No founder variants reported. Carrier frequency is low; prevalence mirrors regional thalassemia distribution.

3. Functional Evidence

Mechanism: Haploinsufficiency due to contiguous gene deletions. Functional assays: HPLC and capillary electrophoresis revealed markedly reduced Hb A and A2 with compensatory HbF increase ([PMID:27134860],[PMID:39640193]). LC-MS/MS quantitation confirmed absent δ and β peptides in homozygous and heterozygous states ([PMID:38212249]). MLPA delineated deletion breakpoints validating gene loss.

4. Conflicting Evidence

No studies have refuted the HBB–delta-beta thalassemia link. Variant effects are consistent across diverse populations.

5. Integration & Conclusion

Genetic and experimental data converge to support a Moderate ClinGen classification for HBB in delta-beta thalassemia, reflecting multiple probands, segregation, and robust functional concordance. Diagnostic assays combining HPLC screening, MLPA, and LC-MS/MS enable accurate detection of these large deletions. Key Take-home: HBB large-deletion analysis is clinically useful for diagnosis and genetic counseling in delta-beta thalassemia.

References

• Journal of clinical and diagnostic research • 2016 • Incidental Identification of Possible Delta-Beta Thalassemia Trait in a Family: A Rare Cause of Elevated Hb F. PMID:27134860
• British journal of biomedical science • 2024 • Homozygous Delta-Beta Thalassaemia With Alpha Thalassaemia and Erythrocytosis- a Rare Case Report. PMID:39640193
• Proteomics • 2024 • Identification of a rare [GγAγδ0]-thalassemia using tandem mass spectrometry. PMID:38212249

Evidence Based Scoring (AI generated)