Diagnostic challenges for a novel SH2D1A mutation associated with X‐linked lymphoproliferative disease. Issue 4 (29th January 2020)

• Record Type: Journal Article
• Authors: Torralba‐Raga, Lamberto; Tesi, Bianca; Chiang, Samuel C. C.; Schlums, Heinrich; Nordenskjöld, Magnus; Horne, AnnaCarin; Henter, Jan‐Inge; Meeths, Marie; Abdelhaleem, Mohamed; Weitzman, Sheila; Bryceson, Yenan
• Is Part Of: Pediatric blood & cancer. Volume 67:Issue 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-01-29
• Subjects: diagnostic assays -- hemophagocytic lymphohistiocytosis -- ITSM -- NK cells -- SAP -- X‐linked lymphoproliferative disease; Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.28184
• Languages: English
• ISSNs: 1545-5009

Abstract

Abstract: Mutations in SH2D1A, encoding the intracellular adaptor signaling lymphocyte activation molecule associated protein (SAP), are associated with X‐linked lymphoproliferative disease type 1 (XLP1). We identified a novel hemizygous SH2D1A c.49G > A (p.E17K) variant in a 21‐year‐old patient with fatal Epstein‐Barr virus infection–associated hemophagocytic lymphohistiocytosis. Cellular and biochemical assays revealed normal expression of the SAP variant protein, yet binding to phosphorylated CD244 receptor was reduced by >95%. Three healthy brothers carried the SH2D1A c.49G > A variant. Thus, data suggest that this variant represents a pathogenic mutation, but with variable expressivity. Importantly, our results highlight challenges in the clinical interpretation of SH2D1A variants and caution in using functional flow cytometry assays for the diagnosis of XLP1.