CYBC1 and Inflammatory Bowel Disease: Genetic and Functional Insights

CYBC1 is a gene known for its role in the regulation of the phagocyte NADPH oxidase complex. Recent studies have expanded the phenotypic spectrum associated with CYBC1 deficiency to include inflammatory bowel disease (IBD). In particular, evidence from multi‐patient studies has demonstrated that loss‐of‐function variants in CYBC1 can predispose individuals to colitis, a key manifestation of IBD. This summary focuses on the association between CYBC1 and IBD, drawing on genetic studies and functional assessments to support diagnostic decision‑making. The disorder in question, IBD, is clinically characterized by chronic inflammation of the gastrointestinal tract. Such a link reinforces the need to consider CYBC1 deficiency in patients presenting with colitis symptoms.

The genetic evidence for this association is robust. In a landmark multi‑patient study, a homozygous loss‑of‑function mutation, c.6C>G (p.Tyr2Ter), was identified in two affected brothers, with imputation analysis in a larger Icelandic cohort revealing six additional homozygotes. These individuals exhibited signs consistent with chronic granulomatous disease and colitis, and statistical analysis yielded a significant association with IBD (P = 8.3e-8; OR = 67.6) (PMID:30361506). Such findings suggest that the recurrent c.6C>G (p.Tyr2Ter) variant not only disrupts protein function but also confers a high risk for developing IBD. The clear segregation of the variant with disease phenotypes across multiple patients further bolsters the genetic argument. Overall, the genetic evidence qualifies as strong by ClinGen standards.

Detailed case reports have further clarified the inheritance and segregation patterns. The affected siblings in the initial study represent familial clustering and provide supporting evidence for autosomal recessive transmission. In addition to the two siblings, the detection of six unrelated homozygotes in the population study underscores the repeatability and penetrance of the mutation. This multi‐patient evidence highlights the importance of considering familial history when evaluating IBD with an underlying immunodeficiency component. The detection of the same loss‑of‑function variant across distinct cases mitigates concerns of sporadic incidence. Consequently, the genetic data substantiate the use of CYBC1 variants for diagnostic stratification in IBD.

Functional studies have provided essential insights into the mechanism of disease. In separate experimental assessments, loss‑of‑function mutations in CYBC1 were shown to markedly reduce the expression of the NADPH oxidase subunit, gp91phox. This reduction impairs the neutrophil oxidative burst, a crucial cellular function, and contributes to the immunological dysregulation observed in patients. Functional assays have corroborated the pathogenic impact of the c.6C>G (p.Tyr2Ter) variant. Notably, one study demonstrated that patient‐derived cells present with a compromised oxidative response, supporting the notion that CYBC1 deficiency underlies the inflammatory process in the gut. Thus, the functional evidence, while moderate in ClinGen scoring, directly links CYBC1 loss‑of‑function to pathogenic mechanisms relevant to IBD.

A coherent narrative emerges when integrating the genetic and functional findings. The strong genetic evidence from multiple homozygote cases, combined with functional assays demonstrating impaired NADPH oxidase activity, provides a compelling argument that CYBC1 loss‑of‑function mutations substantially contribute to the development of IBD. This association is underscored by statistically significant data and mechanistic insights into how reduced gp91phox expression predisposes patients to inflammatory manifestations such as colitis. Although the complete spectrum of clinical consequences may extend beyond IBD, current evidence specifically supports a strong association with inflammatory bowel disease. Moreover, the observed autosomal recessive inheritance pattern aids in risk prediction and familial counseling. The integration of these datasets confirms the diagnostic utility of CYBC1 genetic testing for patients with IBD symptoms.

In summary, the association between CYBC1 (HGNC:28672) and inflammatory bowel disease (MONDO_0005265) is supported by multiple lines of evidence. Both genetic studies and functional assays converge to illustrate a scenario in which homozygous loss‑of‑function mutations, such as c.6C>G (p.Tyr2Ter), lead to impaired NADPH oxidase activity, predisposing individuals to colitis and IBD. This clinically actionable information supports precise diagnostics and could inform therapeutic approaches in patients with complex inflammatory presentations. The assembled evidence not only meets but in some respects exceeds the ClinGen scoring maximum, thereby establishing a strong association.

Key Take‑home sentence: CYBC1 loss‑of‑function mutations play a critical role in the pathogenesis of inflammatory bowel disease, warranting their consideration in diagnostic evaluations and patient management.

References

• Nature Communications • 2018 • A homozygous loss‑of‑function mutation leading to CYBC1 deficiency causes chronic granulomatous disease PMID:30361506
• Clinical Immunology (Orlando, Fla.) • 2023 • Characterization of AR‑CGD female patient with a novel homozygous deletion in CYBC1 gene presenting with unusual clinical phenotype PMID:37055004

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