Genotypic-Phenotypic Correlations in Non-HbE β-Thalassemia Intermedia: A Geographic Systematic Review.
Kavindya Fernando, Shiromi Perera, Anuja Premawardhena
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In 30 seconds
This PRISMA-guided systematic review qualitatively synthesized 21 studies of genotype–phenotype correlations in non-HbE β-thalassemia intermedia, a heterogeneous disorder now included within non-transfusion-dependent thalassemia. The review found regional variation in the genetic factors associated with disease expression: mild β-globin mutations were prominent in Mediterranean populations, HbF-inducing polymorphisms—particularly XmnI—in Middle Eastern populations, and α-globin dosage changes, including triplication, in Asian populations, which showed the greatest molecular heterogeneity. The findings describe patterns in the available evidence rather than establishing causal effects.
Key findings
- Twenty-one studies were included, with evidence synthesized qualitatively by geographic region.
- Mediterranean studies primarily implicated mild β-globin mutations in the phenotype.
- In Middle Eastern populations, HbF-inducing polymorphisms, particularly XmnI, often mitigated severe genotypes.
- Asian populations showed the greatest molecular heterogeneity; α-globin dosage alterations, including triplication, contributed to disease expression.
Why it matters
The review highlights that the genetic contributors to β-thalassemia intermedia may differ across populations, helping explain why similar β-globin mutations can be associated with variable clinical expression. Awareness of these regional patterns can support interpretation of genotype–phenotype variability and guide further research into diagnosis and prognostication, while the qualitative evidence does not establish individual-level predictions.
What to keep in mind
The evidence was synthesized qualitatively across 21 studies, so the review does not provide a pooled quantitative estimate of the effects of specific genetic modifiers.