Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation.

The X-linked form of severe combined immunodeficiency (XSCID) is underdiagnosed because no methods have been available for detecting carriers. Although boys with XSCID are deficient in T cells, female carriers are immunologically normal. Carriers' normal immune function would be expected if all their T cells were derived from precursors whose X chromosome bearing the XSCID mutation was inactivated early in embryogenesis. Using somatic cell hybridization to separate the active and inactive X chromosomes and restriction fragment length polymorphisms to distinguish them, we have determined the lymphocyte X inactivation pattern in XSCID carriers and their female relatives. In the T cells of three carriers, the X chromosome bearing the XSCID mutation was consistently inactive. Nonrandom X inactivation was also found in the T cells of one at-risk female, while two others had normal, random X inactivation. This method constitutes a generally applicable carrier test for XSCID.