THE CRETAN TYPE OF NONDELETIONAL HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN [A-GAMMA-158C-]T] RESULTS FROM 2 INDEPENDENT GENE CONVERSION EVENTS

We report a new type of non-deletional hereditary persistence of fetal hemoglobin that is due to a C --> T transition at position -158, rela tive to the Cap site of the human A gamma-globin gene. This mutation w as identified in three unrelated adult cases presenting slightly eleva ted levels of fetal hemoglobin (Hb F), i.e. 2.9-5.1%, and normal hemat ological indices. Our sequencing results, from both polymerase chain r eaction-amplified and subcloned DNA fragments, indicate that the A gam ma - 158C --> T mutation occurred by two independent gene conversion e vents in the three cases studied. In addition, hematological and molec ular data, including restriction fragment length polymorphism haplotyp ing in the beta-globin gene cluster, extended haplotype analysis insid e the gamma-globin gene region and routine analysis of three tandem re peat loci (D1S80, 3'-HVR/apoB and F8vWf), led us to conclude that the A gamma - 158C --> T mutation in one of the three cases occurred recen tly in the parental germ line (P=99.47%), representing the first examp le of a de novo gene conversion event identified in humans.