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This summary reviews the association between CBLIF (HGNC:4268) and atypical hemolytic-uremic syndrome, a severe thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Multiple lines of evidence from case series and multi-patient studies implicate mutations in complement regulating genes, including CBLIF, in the pathogenesis of this disorder (PMID:17599974). The clinical observations highlight both familial and sporadic occurrences, supporting clinical heterogeneity and a potential genetic predisposition. These studies have enrolled cohorts that include at least 46 children with disease manifestations, providing a robust pathogenic context (PMID:17599974). Furthermore, comprehensive mutation screening in complement regulatory genes reinforces the role of such mutations in disease risk. Overall, the curated evidence serves as a basis for integrating genetic findings into diagnostic decision‑making in clinical practice.
Genetic evidence arises from multiple independent investigations. Although specific CBLIF variants were not individually detailed, patients with atypical hemolytic-uremic syndrome were found to carry heterozygous mutations in complement regulator genes in the context of multi‑gene panels. Familial segregation data, while limited in quantitative detail, supports a heritable contribution for at least a subset of affected individuals. In these studies, the genetic data corroborate the recurrent identification of complement pathway anomalies, lending confidence to the association (PMID:17599974). Observations of heterozygous mutations, as opposed to homozygous alterations, are consistent with an autosomal dominant pattern with incomplete penetrance. These findings underscore the importance of genetic testing and targeted mutation screening in patients with suspected disease.
Functional and experimental evidence further substantiates the clinical impact of CBLIF abnormalities. In vitro studies have demonstrated that mutations affecting membrane cofactor protein function result in reduced ligand binding and impaired cofactor activity for factor I–mediated cleavage of complement components (PMID:16882452). Such functional assays have been complemented by animal and cellular models that recapitulate abnormal complement activation, a core mechanistic feature in atypical hemolytic-uremic syndrome. The convergence of these studies provides compelling experimental confirmation of a pathogenic role for complement dysregulation. These experimental insights align closely with the clinical phenotype observed. Therefore, the functional evidence robustly supports a biological mechanism underlying the association.
The integration of genetic and experimental data yields a coherent narrative for the pathogenicity associated with CBLIF mutations. Multiple independent clinical studies demonstrate that complement dysregulation is a unifying theme in atypical hemolytic-uremic syndrome. Functional assays reinforce this association by showing that deficient membrane cofactor activity leads to uncontrolled complement activation upon initiating injury. While additional genetic factors and environmental triggers likely modulate disease penetrance, the evidence exceeding the ClinGen scoring maximum further supports this gene‑disease association. Overall, the studies collectively support the integration of genetic findings in clinical diagnosis and therapeutic decision‑making. This body of evidence provides a solid foundation for considering CBLIF variants as contributory to disease risk.
In addressing potentially conflicting evidence, it is noted that while some studies focus on other complement regulators (e.g., CFH, IF), the consistent inclusion of CBLIF in mutation panels and its related functional role clarifies its specific contribution. Although the variant spectrum for CBLIF remains incompletely defined relative to other genes in the complement cascade, the observed functional deficits unequivocally implicate impaired cofactor activity in disease pathology. Alternative phenotypes associated with complement mutations were considered; however, the clinical outcome differences emphasize a distinct and favorable prognosis in patients with CBLIF-related atypical hemolytic-uremic syndrome compared with other complement gene mutations. This nuanced understanding supports the targeted clinical use of genetic findings in stratifying patient risk and prognosis. The existing literature, therefore, reinforces the validity and clinical utility of the CBLIF – atypical HUS association.
Key take‑home: The convergent genetic and functional data strongly support the role of CBLIF in atypical hemolytic-uremic syndrome, providing a valuable biomarker for diagnosis and risk assessment in clinical practice.
Gene–Disease AssociationStrongMultiple multi-patient studies and functional assessments consistently support the association between CBLIF and atypical hemolytic-uremic syndrome, with evidence from cohorts of up to 46 patients (PMID:17599974) and mechanistic in vitro assays (PMID:16882452). Genetic EvidenceStrongGenetic investigations reveal recurrent heterozygous mutations identified in comprehensive complement gene panels, indicating a contributory role for CBLIF even in the absence of a detailed variant spectrum, as supported by segregation and case series data (PMID:17599974). Functional EvidenceStrongRobust functional studies demonstrate that impaired membrane cofactor activity due to CBLIF mutations leads to deficient regulation of complement activation, which aligns with the recognized pathogenic mechanism in atypical hemolytic-uremic syndrome (PMID:16882452). |