Concordance of a point mutation 5' to the (G)γ globin gene with (G)γβ⁺ hereditary persistence of fetal hemoglobin in the black population

Hereditary persistence of fetal hemoglobin (HPFH) is a genetically heterogeneous and clinically benign condition characterized by persistent expression of fetal hemoglobin (Hb F) into adulthood. In the (G)γβ⁺ type, no major deletions in the globin gene cluster occur; adult heterozygotes produce approximately 20% Hb F, which results from overproduction of (G)γ chains, with no apparent increase in production from the adjacent (A)γ gene. We have recently described a point mutation 202 base pairs 5' to the cap site of the (G)γ gene in an individual with (G)γβ⁺ HPFH. This mutation abolishes a normal ApaI restriction endonuclease site, and thus can be detected by blotting of genomic DNA. We present here further data on the ApaI mutation: (1) It occurs in six of seven families with (G)γβ⁺ HPFH. (2) In three families, detailed haplotype analysis using 11 polymorphic restriction sites in the β globin cluster has been done. The two that carry the missing ApaI site are identical but the third, which has a normal ApaI pattern, differs from the other two in at least two sites, one of which is a new polymorphic Nco I site between the δ and β globin genes. This suggests the possibility of a different HPFH mutation in the third family. (3) The haplotype of the (G)γβ⁺ HPFH chromosome carrying the ApaI mutation is different from that of 108 β(A) chromosomes of black individuals that have been tested. (4) The (G)γ ApaI site is normal in 61 β(A) and 109 β(S) alleles from non-HPFH black individuals, including 22 who share the same haplotype for the intragenic (G)γ, (A)γ HindIII polymorphisms. These data add support to the possibility that the -202 mutation is actually causative of the (G)γβ⁺ HPFH phenotype.