Thalassemia and Genetic Implications in Pregnancy

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:

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).