Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP)

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency, w hich most often manifests itself after Epstein-Barr virus (EBV) infection. The main clinical phenotypes include fulminant or fatal infectious mononucl eosis, dysgammaglobulinaemia and malignant lymphoma. We have recently clone d the SH2D1A gene, which has been shown to be mutated in similar to 70% of XLP patients. Now we report five novel SH2D1A mutations in patients from fi ve unrelated XLP families. No mutations were found in another three XLP fam ilies. In three boys with early onset non-Hodgkin lymphoma (NHL) from two u nrelated families a deletion of SH2D1A exon 1 and a splice site mutation we re found, respectively. These patients did not show any laboratory or clini cal signs of a previous EBV infection. A fourth EBV-uninfected and unrelate d boy with a stop mutation in the SH2D1A gene shows only signs of dysgammag lobulinaemia. Development of dysgammaglobulinaemia and lymphoma without evi dence of prior EBV infection in four of our patients suggests that EBV is u nrelated to these phenotypes, in contrast to fulminant or fatal infectious mononucleosis. The role of SH2D1A as a putative tumour suppressor gene rema ins to be investigated.