XIAP

Gene Facts

• HGNC Symbol: XIAP (HGNC:592)
• HGNC Name: X-linked inhibitor of apoptosis
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: API3, BIRC4
• Alias symbols: hILP, ILP-1
• %HI: 3.36
• pLI: 0.92
• LOEUF: 0.37
• Cytoband: Xq25
• Genomic Coordinates:

  GRCh37/hg19:	chrX:122993558-123047822
  GRCh38/hg38:	chrX:123859708-123913972

• MANE Select Transcript: NM_001167.4 ENST00000371199.8
• Function: Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis (PubMed:11447297, PubMed:12121969, PubMed:9230442, PubMed:11257230, PubMed:11257231, PubMed:12620238, PubMed:17967870, PubMed:19473982, PubMed:20154138, PubMed:22103349, PubMed:17560374). Acts as a direct caspase inhibitor (PubMed:11257230, PubMed:11257231, PubM... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-4554
• ClinGen Curation ID: CCID:008117
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Yes
  While most males present in infancy or early childhood, there are reports of males with typical infantile presentation of disease with male siblings hemizygous for the same familial variant who are asymptomatic (PMID:22228567 and PMID:20489057). Long term outcome however is unknown.
• Last Evaluated: 07/27/2022

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• X-linked lymphoproliferative disease due to XIAP deficiency

HI Evidence

• PUBMED: 17080092
  Rigaud et al., 2006, reported three large families with several males in multiple generations diagnosed with lymphoproliferative syndrome. Most males in these families developed lymphohystiocytosis, usually but not always related to EBV infection. The clinical phenotype was described as similar to what is seen in patients with SH2D1A mutations, however genetic sequencing of the SH2D1A gene in these families was negative. Mapping studies followed by sequencing revealed that all three families were found to harbor loss of function variants in XIAP. Mothers of affected individuals were found to be asymptomatic heterozygous carriers, and healthy siblings who were tested were found not to carry the variant. Expression of XIAP was not detected in the lysates of lymphocytes in affected individuals.
• PUBMED: 20489057
  Marsh et al., 2010, reported 10 male individuals from eight families and concluded that XIAP deficiency is better defined as an X-linked form of familial hymophagocytic lymphohistiocytosis (HLH), rather than X-linked lymphoproliferative disease (XLP), as nine out of 10 patients developed HLH by eight years of age, with zero cases of lymphoma. In those who were tested (9/10), XIAP protein expression was decreased or undetectable. Of the eight unique variants identified, five represented truncating or single or multi-exon deletions. Five of the 10 individuals presented in infancy, four in the first decade, and one represented an asymptomatic male sibling at four years of age.
• PUBMED: 24942515
  Aguilar et al., 2014, reported 17 male individuals from 11 families with diagnoses of inflammatory bowel disease (IBD), diagnosed between the ages of three months to 41 years, who were found to have hemizygous variants in XIAP. Of the 11 unique variants that were identified, eight represented truncating variants or multi-exon deletions. All 17 individuals had decreased or absent XIAP protein expression. In addition, two female relatives were reported to be affected. X-inactivation studies showed skewing toward the allele carrying the familial variant in both cases, which was not the case in seven unaffected female carriers.
• PUBMED: 25943627
  Dziadzio et al., 2015, reported one large family of Caucasian descent who carried a truncating variant in XIAP and displayed segregation over four generations (at least 8 segregations). Affected males presented with inflammatory bowel disease, though the age of onset and clinical outcomes were highly variable. Additionally, all female carriers but one were affected, with variable gastrointestinal diagnoses and chronic erythema nodosum.

• HI Evidence Comments: Loss of function mutations in XIAP cause X-linked lymphoproliferative syndrome type 2 (XLP2). Males with this diagnosis typically present in infancy with features including hemophagocytic lymphohistiocytosis (HLH), colitis or other gastrointestinal disease, dysgammaglobulinemia, and splenomegaly, however the age of presentation can range into adulthood. Approximately 15% of mutations are large deletions (PMID: 20301580). Generally, males are affected but rarely may be asymptomatic (PMID:20489057; PMID:22228567). Typically females carriers are unaffected, though affected carrier females have been reported with diagnoses of colitis, inflammatory bowel disease, or Crohn's disease (PMID:24942515, PMID:25943627). Affected individuals have absent or significantly reduced XIAP protein expression (PMID:24942515, PMID: 22228567, PMID: 20489057; PMID: 32542393). Several large families have been reported with multiple affected male relatives (PMID: 17080092, PMID:24942515). When tested, typically affected males have inherited the variant from their mother, though occasional reports of de novo inheritance exist (PMID:24572142, PMID:26581487). There is one report of suspected gonadal mosaicism (PMID: 22228567).

NOTE

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 (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity

NOTE

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.