Heterozygous α- and ß-thalassemia (Thalassemia Minor, or “Trait”) are asymptomatic. However, 2 such parents might give birth to a baby with severe homozygous disease.
Beta-Thalassemia inheritance is easy; it involves a single gene locus on chromosome 11. Inheritance follows simple Mendelian principles — if two heterozygous (Bb) parents with β-Thalassemia Minor (or “Trait”) conceive, genotype likelihoods are:
- 25% of offspring homozygous normal (BB) = normal phenotype
- 50% heterozygous (Bb) = β-Thalassemia Minor (asymptomatic)
- 25% homozygous disease (bb) = β-Thalassemia Major (severe, often-fatal, hemolytic Cooley’s Anemia in infancy)
Alpha-Thalassemia is more complicated, involving two genetic loci on Chromosome 16. So we inherit 4 genes, 2 from each parent. Mutations result in deletions of one or both of these genes on one or both of the Chromosome pair. We diagram the Genotypic possibilities:
|Normal 1 Deletion 2 Deletions (Pattern 1) 2 Deletions (Pattern 2) 3 Deletions 4 Deletions||AA / AA Ax / AA Ax / Ax AA / xx Ax / xx xx / xx|
One AA pair represents the 2 normal genes on mother’s chromosome, and the other AA pair represents the 2 normal genes on father’s, etc. An “x” = gene deletion.
Phenotypes are as follows:
- 1 Gene Deletion = “Silent Carrier” or “α-Thalassemia Minima”. Normal H&H, maybe a very slightly decreased MCV (maybe not). Asymptomatic.
- 2 Gene Deletions = α-Thalassemia Minor, or Trait. Slight anemia, slightly decreased MCV. Hemoglobin Electrophoresis may be normal, or show decreased HbA2. Asymptomatic.
- 3 Gene Deletions = Hemoglobin H Disease. Moderate-to-severe hemolytic anemia usually diagnosed in childhood, sometimes as adults.
- 4 Gene Deletions = Bart’s Hemoglobin (Hb Bart’s), not compatible with extra-uterine life, causes stillbirth with hydrops fetalis (except with heroic intrauterine interventions).
Implications to the fetus of the parents’ genotypes: one gene deletion carries no risk to fetus. But if both parents have α-Thal Minor (2 gene deletions), they risk a fetus with xx / xx if both the parents’ deletions occur on the same chromosome (Pattern 2).
- Pattern 2 occurs in Asia (Arabia, Indian subcontinent, SE Asia).
- African-Americans with α-Thal Minor carry 1 deletion on each chromosome (Pattern 1), so their children will only have asymptomatic α-Thal Minor like they do.
- An African-American with α-Thal Minor (Ax / Ax) conceiving with an Asian (AA / xx) carry a 50% chance of their baby having Ax / xx (Hemoglobin H Disease).