ClinGen Dosage Sensitivity Curation Page

SH2D1A

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11049992 Sumegi et al (2000) reported that analysis of 35 families from the X-linked lymphoproliferative disease (XLP) Registry revealed 28 different mutations in 34 families, including large genomic deletions (n = 3), small intragenic deletions (n = 10), splice-site (n = 3), nonsense (n = 3), and missense (n = 9) mutations.
11159547 Arico et al (2001) analyzed 25 patients diagnosed with HPLH for germline mutations in the SH2D1A gene. They identified 4 patients with XLP and carried a mutation in the SH2D1A gene. Two had hemizygous deletions encompassing SH2D1A exon 1 and 2 had nonsense mutations.
31144249 Nademi et al (2019) repotted three siblings from a non-consanguineous family of Yemeni origin with hemizygous deletions of exon 2 of the SH2D1A gene. All three patient were diagnosed with XLP but manifested different phenotypes at different ages.

Haploinsufficiency phenotype comments:

X-linked lymphoproliferative syndrome (XLP), or Duncan disease, is a primary immunodeficiency characterized by severe immune dysregulation often after viral infection, typically with Epstein-Barr virus (EBV), predominantly presented with hemophagocytic lymphohistiocytosis (HLH), dysgammaglobulinemia and lymphoproliferative disease. Loss of function mutations in SH2D1A cause XLP. More than 113 SH2D1A pathogenic variants have been identified to contribute to XLP-associated phenotype: ~25% are splicing defects or frameshift variants and ~25% are large deletion of one or more exons or the entire gene (HGMD, PMID: 32461654; GeneReviews). Multiple functional studies (PMID: 11404475; 15774582;18843362) including SH2D1A knock out mice model further demonstrated the association between SH2D1A deficiency and XLP-related phenotype. PMID: 15774582 Morra et al (2005) found that mice lacking Sh2d1a had severely impaired primary and secondary responses of all Ig subclasses to specific antigens, even in the absence of viral infection. both defective T and B cells exist in the absence of SH2D1A mice model, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Focal duplication of SH2D1A is not identified.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.