LINKAGE ANALYSIS OF THE HEMOGLOBIN-F DETERMINANT(S) IN AN AUSTRALIAN HEMOGLOBIN LEPORE (BOSTON) KINDRED

Genetic determinants that influence the levels of fetal hemoglobin (Hb F) in a single Australian kindred with heterozygous Hb Lepore (Boston ) were sought. There were 22 affected individuals, some of whom had hi gh Hb F and others with Hb F levels within the normal range. Family me mbers were typed for restriction fragment length polymorphisms (RFLPs) associated with the beta-globin gene complex and the nearby genetic m arkers D11S12, INS, HRAS, and PTH. Prior to linkage analysis, a cohort of 54 unrelated Hb Lepore heterozygotes was analyzed to establish the distribution of Hb F levels measured by alkaline denaturation (Hb F(A D)). An Hb F level of > 2.0% was used as the cutoff point for linkage analysis of the putative hereditary persistence of fetal hemoglobin (H PFH) determinant(s) in this kindred. Positive peak lod scores were obt ained for the entire pedigree between the HPFH determinant and Hb Lepo re (Z(m+f) = 2.35 at theta = 0.15) and the beta-globin cluster (HBBC) (Z(m+f) = 2.38 at theta = 0.20) marker loci, indicating the possibilit y of an independent HPFH gene at some distance from the beta-globin ge ne cluster. However, most of these lod scores result from the non-Hb L epore members of the family who, with one exception, do not have high Hb F, and when only those affected with Hb Lepore were analyzed the lo d score values at these loci fell to small positive values (< 1.0). Th ese data do not support an independent cosegregating HPFH determinant separate from the Hb Lepore locus in this pedigree. The results favor a pleiotropic effect of the Hb Lepore lesion itself influencing Hb F l evels by genetic or environmental factors not yet elucidated.