Mapping of a gene for X-linked agammaglobulinemia and evidence for genetic heterogeneity

X-linked agammaglobulinemia (XLA) is a severe humoral immunodeficiency disease of man. The inheritance of the disease is X-linked recessive. Female carriers can not be distinguished by immunologic assays. We investigated the localization of the disease gene on the X chromosome, utilizing nine polymorphic X chromosomal markers. In a single eight generation pedigree we found close linkage of the disease gene to the restriction fragment length polymorphism (RFLP) recognized by the DNA probe p19-2; the maximum lod score was 3.30 at a recombination fraction of 0.06. Addition of the lod scores for p19-2 obtained from seven other XLA pedigrees did not show the expected increase of the total score. This suggested genetic heterogeneity. We used the p19-2 marker as a reference point to search for pedigrees which had the disease gene at a different location. One pedigree provided a lod score of -3.14 at a recombination fraction of 0.06 with the p19-2 marker. We postulate that XLA is not a single genetic entity.