Carrier Detection in X-Linked Agammaglobulinemia by Analysis of X-Chromosome Inactivation

We used a recently developed strategy to analyze patterns of X-chromosome inactivation in human cell populations in order to study female members of families with X-linked agammaglobulinemia — i.e., to detect the carrier state and to test the hypothesis that the disorder results from a defect intrinsic in the development of B cells. According to this strategy, recombinant-DNA probes simultaneously detect restriction-fragment–length polymorphisms and patterns of methylation of X-chromosome genes. Random X-inactivation patterns were observed in isolated peripheral-blood granulocytes, T lymphocytes, and B lymphocytes of women who were not carriers. In contrast, one of the two X chromosomes was preferentially active in the peripheral B cells, but not the T cells or granulocytes, of three carriers of the disorder. This observation strongly supports the hypothesis that X-linked agammaglobulinemia results from an intrinsic defect in B-cell development. Moreover, the analysis described here can be used for direct identification of carriers in families with this disease. (N Engl J Med 1987; 316:427–31.), DURING embryogenesis, one of the two X chromosomes in the somatic cells of every female is randomly inactivated.¹ Thus, each cell from a female carrier of an X-linked disease has the mutant gene causing the disease, either on the active X chromosome or on the inactive X chromosome. In effect, these carriers have two subpopulations of cells. Cells with the mutant gene on the active X chromosome are functionally equivalent to cells from males with the disease; the other subpopulation of cells, with the normal gene on the active X chromosome, is normal. This functional mosaicism, if identified, could be….