Diagnostic challenges for a novel SH2D1A mutation associated with X-linked lymphoproliferative disease

Pediatr Blood Cancer. 2020 Apr;67(4):e28184. doi: 10.1002/pbc.28184. Epub 2020 Jan 29.

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.

Keywords: ITSM; NK cells; SAP; X-linked lymphoproliferative disease; diagnostic assays; hemophagocytic lymphohistiocytosis.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Substitution
  • Epstein-Barr Virus Infections* / genetics
  • Epstein-Barr Virus Infections* / metabolism
  • Fatal Outcome
  • Gene Expression Regulation, Leukemic
  • Hemizygote*
  • Herpesvirus 4, Human* / genetics
  • Herpesvirus 4, Human* / metabolism
  • Humans
  • Lymphohistiocytosis, Hemophagocytic* / genetics
  • Lymphohistiocytosis, Hemophagocytic* / metabolism
  • Lymphohistiocytosis, Hemophagocytic* / virology
  • Lymphoproliferative Disorders* / genetics
  • Lymphoproliferative Disorders* / metabolism
  • Lymphoproliferative Disorders* / virology
  • Male
  • Mutation, Missense*
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / metabolism
  • Signaling Lymphocytic Activation Molecule Associated Protein* / biosynthesis
  • Signaling Lymphocytic Activation Molecule Associated Protein* / genetics
  • Signaling Lymphocytic Activation Molecule Family / genetics

Substances

  • CD244 protein, human
  • Neoplasm Proteins
  • SH2D1A protein, human
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family