GγAγ(β+) hereditary persistence of fetal hemoglobin: The Gγ – 158 C → T mutation in cis to the − 175 T → C mutation of the Aγ-globin gene results in increased Gγ-globin synthesis

Hereditary persistence of fetal hemoglobin (HPFH) can be generally classified into deletional and nondeletional forms. The family described in the present study has characteristics of both types of HPFH. The proband is a healthy 30-year-old black woman. Analysis of her hemoglobin revealed 40.4% HbS, 40.9% HbF (^Gγ/^Aγ ratio 0.53), 16.8% HbA, and 1.9% HbA₂. All of her hematologic indices were normal, and the distribution of HbF in her red cells was pancellular. Family studies demonstrated that the proband has one chromosome 11 bearing the β^s-globin gene and the other bearing a ^Gγ^Aγ(β⁺) HPFH determinant in cis to the β^A-globin gene. Gene mapping studies of the region between the ^Gγ- and β-globin genes were normal. However, when the ^Aγ and ^Gγ promoters were amplified by polymerase chain reaction (PCR) and sequenced, the ^Aγ promoter was found to have the T→C mutation at ?175, and the ^Gγ promoter region was found to have the C→T mutation at ?158. The ?158 C→T mutation has been associated with elevated ^Gγ levels and high HbF in hemolysis, although its role in causing these effects is unclear. The present study suggests that this mutation can also enhance ^Gγ-globin expression in cis to the ?175 T→C mutation in the absence of hemolysis. We suggest that the alteration of the ^Aγ gene octamer binding site by the ?175 mutation, as well as the loss of a putative ^Gγ “silencer” caused by the ?158 mutation may account for this phenotype. We propose calling these linked mutations the ^Gγ^Aγ(β⁺) HPFH. © 1993 Wiley-Liss, Inc.