Concordance of a point mutation 5' to the (A)γ-globin gene with (A)γβ⁺ hereditary persistence of fetal hemoglobin in Greeks

In the Greek (A)γβ⁺ type of hereditary persistence of fetal hemoglobin (HPFH), adult heterozygotes produce about 20% fetal hemoglobin (HbF), which is predominantly of the (A)γ chain variety. The affected β-globin gene cluster produces near normal amounts of β-like globin, but in a (A)γ to β ratio of 20:80 instead of 0.5:99.5. Gelinas et al and Collins et al have shown a G to A change 117 nucleotides 5' to the (A)γ gene in two Greeks with (A)γβ⁺ HPFH. To demonstrate that this change is not a neutral polymorphism, we carried out hybridization with oligonucleotide probes (19mers) specific for the normal and the mutant sequences. While normal probe identified the (A)γ fragment in genomic DNA of all subjects studied, mutant probe was positive only in Greeks with (A)γβ⁺ HPFH. In sum, 108 β-globin gene clusters of individuals without HPFH were negative when tested with mutant probe, but all 11 affected individuals of six families with Greek (A)γβ⁺ HPFH (two previously sequenced and four new families) were positive with mutant probe. These data support the conclusion that the -117 mutation is causative of (A)γβ⁺ HPFH in Greeks.