Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: BIRC3

Green List (high evidence)

Comment on list classification: As reviewed by Boaz Palterer, there is sufficient evidence available (seven unrelated families with monoallelic variants and three unrelated families with biallelic variants) for the association of of BIRC3 with inflammatory bowel disease. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 30 Jul 2026, 5:09 p.m. | Last Modified: 30 Jul 2026, 5:09 p.m.

Panel Version: 9.44

PMID:42335979 (2026) reported the identification of rare and damaging BIRC3 variants in 14 patients from 10 unrelated families with Crohn's disease (CD) diagnosed between infancy and adulthood. They carried 8 distinct BIRC3 variants — 5 heterozygous missense/ nonsense variants (p.H312Y - recurrent in 2 families and de novo in the index patient), p.T35A, p.P266R, p.C557X, p.D530H) causing pediatric- to adult-onset CD (age range <1 to 31 years), and 3 homozygous nonsense/ frameshift variants (p.Y522X, p.C588Y, p.X605Rext*10) in sibling pairs from consanguineous families, causing infantile-onset CD.

Functional studies showed that BIRC3 (cIAP2) deficiency impairs RIPK1 ubiquitylation, causing RIPK1 autophosphorylation, resulting in increased epithelial cell death. Knock‑in cIAP2 (H312Y/+) mice and ciap1‑deficient zebrafish developed or exacerbated colitis, transcriptome analysis of mice organoids and zebrafish showed that BIRC3 deficiency led to inappropriate sustained activation of TNF‑responsive genes even without stimuli, and intestinal inflammation in BIRC3‑deficient models was attenuated by small‑molecule inhibition of RIPK1 or caspases.

This gene has not yet been associated with relevant phenotypes in OMIM or ClinGen (last accessed 30 July 2026).

Created: 30 Jul 2026, 5:04 p.m. | Last Modified: 30 Jul 2026, 5:10 p.m.

Panel Version: 9.44

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
inborn error of immunity, MONDO:0003778; Crohn disease, MONDO:0005011

Publications

• 42335979

Green List (high evidence)

Qi Li et al. described 14 patients from 10 unrelated families with monoallelic and biallelic variants in BIRC3 presenting with CD. Biallelic variants present more severe and earlier. Extensive funtional validation including zebrafish and mice models, recapitulating phenotype
https://www.gastrojournal.org/article/S0016-5085(26)06946-5/fulltext
Sources: Literature

Created: 24 Jun 2026, 3:20 p.m.

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Inflammatory bowel disease; IBD; Crohn's disease