HBB – Sickle Cell Anemia

Sickle cell anemia (MONDO:0011382) is a severe autosomal recessive hemoglobinopathy caused by a homozygous missense variant in the HBB gene. The canonical mutation c.20A>T (p.Glu7Val) disrupts the β-globin chain, promoting polymerization of deoxygenated hemoglobin S and leading to sickling of erythrocytes, chronic hemolytic anemia, vaso-occlusive crises, splenomegaly and end-organ damage ([PMID:29345446]).

The clinical validity of this gene–disease relationship is Definitive. It is supported by >1,000 unrelated affected individuals across diverse populations, consistent autosomal recessive segregation, and decades of concordant biophysical and clinical studies. Families with homozygous c.20A>T genotype show fully penetrant disease, while carriers are asymptomatic (recessive inheritance) ([PMID:2283693]).

Genetic Evidence: Sickle cell anemia follows autosomal recessive inheritance. Segregation studies in multi-generation pedigrees demonstrate co-segregation of homozygous c.20A>T alleles with disease. Case series report hundreds of probands with homozygous c.20A>T and compound heterozygotes (e.g., c.20A>T/c.19G>A) exhibiting classic sickle cell phenotypes ([PMID:37113902]). Founder effects in West African and Caribbean populations explain high carrier frequencies (~8–10%).

Variant Spectrum: The predominant variant is c.20A>T (p.Glu7Val), accounting for most cases worldwide. Other rare β-chain substitutions (e.g., c.19G>A (p.Glu7Lys), c.364G>A (p.Glu122Lys)) contribute to milder S-chain syndromes or compound phenotypes ([PMID:31983541]). Recurrent haplotypes (Benin, Senegal, Arab-Indian) modulate fetal hemoglobin levels and clinical severity.

Functional Evidence: Biophysical studies reveal that p.Glu7Val induces hydrophobic β6(A3) valine contacts, triggering polymerization under hypoxic conditions ([PMID:9182548]). Recombinant and animal models reproduce erythrocyte sickling and vaso-occlusion. Gene therapy trials using lentiviral antisickling β-globin demonstrate sustained clinical remission, confirming the pathogenic mechanism ([PMID:28249145]).

Conflicting Evidence: Heterozygous carriers (trait) are typically asymptomatic, underscoring recessive inheritance. Co-inheritance of α-thalassemia, HPFH or modifiers (BCL11A, HBS1L-MYB) alters phenotype severity but does not refute the primary HBB association ([PMID:18667698]).

Conclusion: The association between HBB and sickle cell anemia is well established, with clear genotype–phenotype correlation, robust segregation and extensive functional validation. Genetic testing for c.20A>T is essential for diagnosis, carrier screening, and guiding curative therapies including gene editing. Key take-home: Homozygosity for HBB c.20A>T (p.Glu7Val) predicts classic sickle cell anemia requiring early intervention.

References

• American journal of physical anthropology • 2000 • From a dry bone to a genetic portrait: a case study of sickle cell anemia. PMID:10640943
• Journal of tropical pediatrics • 1990 • Case studies on haemoglobin S heterozygotes with severe clinical manifestations. PMID:2283693
• PLoS One • 2019 • Use of an automated pyrosequencing technique for confirmation of sickle cell disease. PMID:31830127
• The Journal of Biological Chemistry • 1997 • Influence of the A helix structure on the polymerization of hemoglobin S. PMID:9182548
• The New England Journal of Medicine • 2017 • Gene Therapy in a Patient with Sickle Cell Disease. PMID:28249145
• Proceedings of the National Academy of Sciences of the United States of America • 2008 • DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. PMID:18667698

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