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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 | BIRC3 |
Achchuthan Shanmugasundram changed review comment from: 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, 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).; to: 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). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 | BIRC3 | Achchuthan Shanmugasundram Classified gene: BIRC3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 | BIRC3 | Achchuthan Shanmugasundram Added comment: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 | BIRC3 | Achchuthan Shanmugasundram Gene: birc3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.43 | BIRC3 | Achchuthan Shanmugasundram Phenotypes for gene: BIRC3 were changed from Inflammatory bowel disease; IBD; Crohn's disease to inborn error of immunity, MONDO:0003778; Crohn disease, MONDO:0005011 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.42 | BIRC3 | Achchuthan Shanmugasundram Publications for gene: BIRC3 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 | BIRC3 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: BIRC3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 | BIRC3 | Achchuthan Shanmugasundram reviewed gene: BIRC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 42335979; Phenotypes: inborn error of immunity, MONDO:0003778, Crohn disease, MONDO:0005011; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.16 | BIRC3 |
Boaz Palterer gene: BIRC3 was added gene: BIRC3 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: BIRC3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Phenotypes for gene: BIRC3 were set to Inflammatory bowel disease; IBD; Crohn's disease Penetrance for gene: BIRC3 were set to unknown Review for gene: BIRC3 was set to GREEN Added comment: 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 |
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