The Cretan type of non-deletional hereditary persistence of fetal hemoglobin [Aγ–158C→T] results from two independent gene conversion events

Abstract

We report a new type of non-deletional hereditary persistence of fetal hemoglobin that is due to a C→T transition at position –158, relative to the Cap site of the human Aγ-globin gene. This mutation was identified in three unrelated adult cases presenting slightly elevated levels of fetal hemoglobin (Hb F), i.e. 2.9–5.1%, and normal hematological indices. Our sequencing results, from both polymerase chain reaction-amplified and subcloned DNA fragments, indicate that the Aγ–158C→T mutation occurred by two independent gene conversion events in the three cases studied. In addition, hematological and molecular data, including restriction fragment length polymorphism haplotyping in the β-globin gene cluster, extended haplotype analysis inside the γ-globin gene region and routine analysis of three tandem repeat loci (D1S80, 3′-HVR/apoB and F8vWf), led us to conclude that the Aγ–158C→T mutation in one of the three cases occurred recently in the parental germ line (P=99.47%), representing the first example of a de novo gene conversion event identified in humans.