SH2D1A was reported as the gene associated with X-linked lymphoproliferative syndrome in 1998 simultaneously by three different groups (PMID 9811875, 9771704, 9774102). First described clinically in 1975 (PMID 48119), X-linked lymphoproliferative disease due to SH2D1A deficiency (known as XLP1) is characterised as one of fulminant infectious mononucleosis, lymphoproliferative disorders or dysgammaglobulinaemia, generally developing after first exposure to EBV. Patients may have other autoimmune features such as aplastic anaemia, vasculitis and colitis. Since the discovery of the SH2D1A gene, many genetic variants spanning the length of the gene have been described in affected patients, including large deletions, splice-site mutations, nonsense and missense mutations (see PMID 11049992 for a description of 35 families with at least two affected individuals in each family). The mechanism is known to be loss of function. Included in this curation are 6 variants reaching the maximum scorable genetic evidence (PMID 11049992, PMID 9811875, PMID 9774102, PMID11159547, PMID 23829589, PMID 20632414). This gene-disease association is supported by experimental evidence, including animal models, expression studies and gene transfer rescue studies (PMID 12966553, 9774102, 29705247). *SH2D1A *encodes of SAP, a protein basally expressed in NK and T cells (PMID 9774102), and interacts with SLAM and other members of the CD2 subfamily of cellular receptors (PMID 15661030 for summary). Deletion of exon 2 of the sap gene in mice recapitulates the phenotype seen in humans with absence of SAP protein, susceptibility to murine gammaherpesvirus-68 and dysgammaglobulinaemia (PMID 12966553). Transduction of wildtype SH2D1A in patient T-cells with a lentiviral vector restores SAP expression and rescues defective T-follicular helper cell function and cytotoxicity (PMID 29705247). HSCT is a curative option in patients with XLP1, and lentiviral gene therapy has shown promising results in both murine models and patient cells (PMID 30459818, PMID 39309261, PMID 23223356). Taken together, the association between SH2D1A and X-linked lymphoproliferative disease due to SH2D1A deficiency is definitive.
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