Elevated Hemoglobin F in an African American Girl with HbS/β Thalassemia: Unraveling the Mechanism.

Factors controlling hemoglobin F production beyond the neonatal period are poorly understood; however, unraveling the mechanisms underlying hereditary persistence of fetal hemoglobin (HPFH) could lead to therapies for β-thalassemia and sickle cell disease. We identified a non-anemic 5 year old girl with Hbs S, F, and A. Investigation revealed elevated HbF in the mother and paternal sickle trait. More than 90% of the gamma globin chains in the daughter were Gγ. Mother and daughter share the common -29 β thalassemia mutation, but have normal MCVs.

We set out to determine:

1. Whether a thalassemia trait explains the MCVs in the mother and child.

2. Whether increased HbF is due to γ globin promoter mutations linked to the −29 β thalassemia mutation.

A duplex PCR strategy was used to genotype family members for the common African −3.7 kb α-thalassemia deletion. Our studies show that the mother is heterozygous for the a globin −3.7 kb deletion while the father and child are homozygous for the wild type α globin locus. The upstream region (−627 to −5) of the Gγ-globin genes of each family member were amplified and the PCR products were digested with the Xmn1 restriction enzyme to determine whether the Xmn1 polymorphism ( C→T at position −158) contributed to the increased fetal hemoglobin. None of the family members had this polymorphism. Sequencing of the upstream region of the Gγ gene revealed that the patient is homozygous for a novel mutation (A →G) at position −309 for which both parents are heterozygous. In summary we describe a novel Gγ gene −309 A →G mutation in association with elevated HbF; further research is in progress to determine if this polymorphism contributes to the patient’s elevated fetal hemoglobin.