CYBC1 – Chronic Granulomatous Disease

This summary details the association between CYBC1 and chronic granulomatous disease, a severe immunodeficiency characterized by recurrent infections and immune dysregulation. Multiple independent studies have reported loss‐of‑function mutations in CYBC1 that impair the NADPH oxidase system. The evidence spans single case reports to multi‐patient genetic studies, each demonstrating a consistent autosomal recessive inheritance pattern. In these reports, affected individuals present with reduced gp91phox expression and functional deficits in neutrophils and monocytes. Familial segregation and recurrence of the identified variant further support the causal role of CYBC1. This robust dataset provides significant support for diagnostic decision‑making and therapeutic strategizing.

Genetic evidence for the gene–disease association is compelling, with strong support from a total of nine probands (PMID:37055004) and clear familial segregation noted in multi‐patient studies (PMID:30361506). The mode of inheritance is autosomal recessive, and additional affected relatives have been noted in at least two separate families. A key variant that illustrates this association is c.10C>T (p.Gln4Ter), which has been identified in affected individuals. This variant is a representative loss‑of‑function mutation that disrupts protein expression, consistent with the phenotype of chronic granulomatous disease. The variant’s HGVS nomenclature is meticulously reported, ensuring reproducibility and clarity in genetic testing. The recurrent identification of loss‐of‐function alleles highlights the genetic consistency underlying the disorder.

Functional studies provide essential insights that complement the genetic findings. Assays have demonstrated that mutations in CYBC1 lead to a failure of CYBC1 protein expression and a corresponding abnormality in the NADPH oxidase complex. In patient-derived neutrophils and monocytes, impaired gp91phox function has been documented, which clearly mirrors the clinical immunodeficiency observed. Furthermore, these studies indicate that the loss of CYBC1 protein expression results in a compromised oxidative burst. Such functional deficits have been corroborated by in vitro assessments and rescue experiments that validate the pathogenic mechanism. Overall, the experimental evidence reinforces the conclusion that CYBC1 deficiency is central to the disease pathology.

The multi-patient studies further consolidate the association by documenting both case reports and series that include familial segregation data. In one study, two affected brothers and six additional homozygotes exhibited clinical features consistent with chronic granulomatous disease (PMID:30361506). This familial clustering underscores the autosomal recessive inheritance pattern and strengthens the genetic evidence. Detailed mutation analysis across these patients confirms that loss-of-function variants in CYBC1, including c.10C>T (p.Gln4Ter), consistently disrupt the expression of the NADPH oxidase complex. These studies not only provide statistical weight but also link the molecular defect with the heterogeneous clinical presentation. The replication of these findings across independent cohorts reinforces the clinical relevance of CYBC1 testing in suspected cases.

Integrating both genetic and functional data provides a coherent narrative that establishes the causal link between CYBC1 mutations and chronic granulomatous disease. The strong genetic evidence, underscored by multiple probands carrying loss-of-function mutations, is complemented by functional assays that demonstrate impaired immune cell function. This convergence of data across different study designs indicates that CYBC1 plays a crucial role in the pathogenesis of the disease. Although additional evidence exists beyond the ClinGen scoring maximum, the available data are sufficient to support a strong clinical association. Clinicians and commercial test developers can rely on these findings to improve diagnostic accuracy and guide patient management. Key take‑home: CYBC1 deficiency is a definitive contributor to AR‑CGD, and its evaluation should be integrated into clinical diagnostic workflows.

References

• 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
• Nature communications • 2018 • A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease PMID:30361506
• Blood cells, molecules & diseases • 2021 • Hematologically important mutations: The autosomal forms of chronic granulomatous disease (third update) PMID:34547651

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