Foundations · Year 1 · from Foundations
Case 2: Alpha-Thalassemia (Splicing Mutation)
Clinical Image
Source: Wikipedia - Alpha-thalassemia - CC BY-SA 3.0
Case Presentation
A 25-year-old pregnant woman of Southeast Asian descent is found to have microcytic anemia (hemoglobin 9.8 g/dL, MCV 68 fL) on routine prenatal labs. Iron studies are normal, ruling out iron deficiency. Hemoglobin electrophoresis shows a normal pattern but reveals Hb H inclusions on supravital staining, consistent with hemoglobin H (HbH) disease, a form of alpha-thalassemia. Genetic testing confirms three alpha-globin gene deletions (--/-alpha), leaving only one functional alpha-globin gene. The genetic counselor explains that one of her deletional alleles (alpha-T) actually results from a splicing mutation rather than a simple deletion: a point mutation at the donor splice site of intron 1 creates an abnormal splice site that leads to aberrant mRNA processing and no functional protein. The father is tested and found to be an alpha-thalassemia carrier (two gene deletions, --/alpha-alpha). There is a 25% risk their child could inherit deletions from both parents resulting in Hb Bart's hydrops fetalis, a condition incompatible with life. Prenatal diagnosis is offered via chorionic villus sampling.
Key Learning Points
- Splice site mutations can produce thalassemia phenotypes even without gene deletions; mutations destroying the canonical GU donor or AG acceptor sites lead to aberrant splicing and non-functional mRNA
- The consequences of splice mutations include exon skipping, intron retention, and cryptic splice site activation, all potentially producing abnormal or absent protein
- Approximately 15-50% of all disease-causing mutations affect splicing, making this one of the most common mechanisms of pathogenic variation