SH2D1A – X-linked lymphoproliferative disease due to SH2D1A deficiency

X-linked lymphoproliferative disease type 1 (XLP1) is a rare X-linked recessive immunodeficiency characterized by extreme susceptibility to Epstein–Barr virus and often presenting as hemophagocytic lymphohistiocytosis (HLH) (PMID:29649976). Causative hemizygous variants in SH2D1A, encoding the SLAM-associated protein (SAP), disrupt T and NK cell signaling, leading to immune dysregulation and high mortality without hematopoietic stem cell transplantation (HSCT).

Genetic evidence includes 33 Japanese patients from 21 families identified by combined flow cytometry and sequencing (PMID:22433061), five Chinese probands with distinct SH2D1A mutations (PMID:25044636), and multiple singleton case reports of nonsense (c.300T>A) (PMID:29649976), frameshift (c.251_255del) (PMID:28231257), and complex structural variants causing exon skipping (PMID:35092357). Maternal segregation analyses confirm X-linked recessive inheritance with unique private alleles in each kindred.

The variant spectrum comprises truncating mutations (n>10) including c.300T>A (p.Tyr100Ter), frameshifts (e.g. c.251_255del (p.Ile84SerfsTer18)), complex deletions/inversions, and missense changes (c.20A>G (p.Tyr7Cys)) without evidence of founder alleles. Clinical manifestations range from EBV-triggered HLH with splenomegaly (HP:0001744) to dysgammaglobulinemia (HP:0002961), B-cell lymphoma (HP:0012191), and recurrent infections (HP:0002719).

Functional studies demonstrate that SH2D1A mutations disrupt the SH2 domain structure (PMID:10694488), abrogate SAP binding to SLAM, 2B4 and CD244 (e.g. p.Gly16Asp) (PMID:15841490), and induce inhibitory 2B4 signaling with impaired NK cell cytotoxicity (PMID:24985396). Rescue experiments in SAP-deficient cells confirm loss-of-function as the primary pathogenic mechanism.

A SH2D1A variant c.49G>A (p.Glu17Lys) illustrates variable expressivity, with reduced CD244 binding but normal SAP levels in both affected and healthy carriers (PMID:31994322), underscoring challenges in single-assay diagnostics.

Collectively, robust genetic and experimental data support a Strong clinical validity classification. Early molecular screening of SH2D1A is critical for diagnosis, guiding HSCT, and improving survival in XLP1.

References

• Pediatric Allergy and Immunology • 2012 • Clinical features and outcome of X-linked lymphoproliferative syndrome type 1 (SAP deficiency) in Japan identified by the combination of flow cytometric assay and genetic analysis. PMID:22433061
• Pediatric Blood & Cancer • 2014 • Clinical and molecular characteristics of Chinese patients with X-linked lymphoproliferative syndrome type 1. PMID:25044636
• BMC Medical Genetics • 2018 • Identification of a novel nonsense mutation in SH2D1A in a patient with X-linked lymphoproliferative syndrome type 1: a case report. PMID:29649976
• PLoS One • 2017 • Targeted sequencing identifies a novel SH2D1A pathogenic variant in a Chinese family: Carrier screening and prenatal genetic testing. PMID:28231257
• Molecular Genetics & Genomic Medicine • 2022 • Exon skipping caused by a complex structural variation in SH2D1A resulted in X-linked lymphoproliferative syndrome type 1. PMID:35092357
• Biochemical and Biophysical Research Communications • 2000 • Structural basis for SH2D1A mutations in X-linked lymphoproliferative disease. PMID:10694488
• Human Mutation • 2005 • Characterization of a new disease-causing mutation of SH2D1A in a family with X-linked lymphoproliferative disease. PMID:15841490
• The Journal of Allergy and Clinical Immunology • 2014 • Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis. PMID:24985396
• Pediatric Blood & Cancer • 2020 • Diagnostic challenges for a novel SH2D1A mutation associated with X-linked lymphoproliferative disease. PMID:31994322

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