Diagnosis of X-linked lymphoproliferative disease by analysis of SLAM-associated protein expression

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency in which affected boys show abnormal responses to Epstein-Barr virus infec tion. The gene defective in XLP has been identified and designated SH2D1A a nd encodes a protein termed SLAM-associated protein (SAP). Mutation analysi s in individuals with typical XLP presentations and family histories has on ly detected abnormalities in approximately 60% of patients. Thus, genetic a nalysis alone cannot confirm a diagnosis of XLP. We have developed a SAP ex pression assay that can be used as a diagnostic indicator of XLP We show th at SAP is constitutively expressed in normal individuals, in patients with severe sepsis and in patients with other primary immunodeficiencies. In six XLP patients, four with classical and two with atypical presentations, SAP expression was absent. in the latter two, who were previously assigned as having common variable immunodeficiency (CVID), the diagnosis of XLP was in itially made using the protein expression assay. In two further patients in whom no mutation could be detected by genetic analysis, lack of SAP expres sion strongly suggests that these individuals have XLP. We therefore sugges t that XLP should be suspected in certain boys previously diagnosed as havi ng CVID and recommend that patients are investigated both by genetic analys is of SH2DIA and by expression of SAP protein.