CFHR3 – Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy driven by dysregulation of the alternative complement pathway. Complement factor H–related protein 3 (CFHR3), encoded by HGNC:16980, forms part of the regulator cluster on chromosome 1q32. Homozygous deletions or rare coding variants in CFHR3, often occurring in concert with CFHR1 deficiency, have been repeatedly linked to susceptibility for aHUS (PMID:18006700).

Clinical evidence includes multiple cohorts and case series demonstrating that 11% of juvenile aHUS patients with complete CFHR3/CFHR1 deficiency harbored pathogenic autoantibodies against CFH (n=147; PMID:18006700) and that homozygous CFHR3/CFHR1 deletion markedly increases aHUS risk (odds ratio 3.61; PMID:27929404). A homozygous missense variant, c.424C>T (p.Arg142Cys), was identified in a Chinese aHUS patient and correlated with reduced C3 levels and poor renal outcomes (PMID:27064621).

Inheritance follows an autosomal recessive pattern for CFHR3 deficiency, requiring biallelic deletions or homozygosity for rare variants. While familial segregation studies are limited, the consistent finding of homozygous CFHR3/CFHR1 loss in unrelated probands underscores a robust genetic predisposition; no multiplex pedigrees with segregating CFHR3 variants have yet been reported.

Functional assays confirm that CFHR3 deficiency predisposes to formation of CFH autoantibodies and impaired complement regulation. Plasma from patients with CFHR3/CFHR1 deletions shows enhanced complement activation and hemolytic activity in vitro (PMID:19531976), and CFHR3 competes with CFH for binding sites on damaged surfaces, modulating the threshold for complement overactivation (PMID:33777036).

No major conflicting studies have disputed the association, although precise penetrance varies by cohort and additional complement gene variants may modulate clinical expression. The collective data support a Strong ClinGen clinical validity classification.

Key Take-home: Testing for homozygous CFHR3 deletions and rare CFHR3 variants, alongside CFH autoantibody screening, provides critical diagnostic and prognostic insight in aHUS and informs immunomodulatory and complement‐targeted therapies.

References

• PLoS genetics • 2007 • Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PMID:17367211
• Blood • 2008 • Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. PMID:18006700
• International journal of environmental research and public health • 2016 • Association among Complement Factor H Autoantibodies, Deletions of CFHR, and the Risk of Atypical Hemolytic Uremic Syndrome. PMID:27929404
• American journal of nephrology • 2016 • Comprehensive Analysis of Complement Genes in Patients with Atypical Hemolytic Uremic Syndrome. PMID:27064621
• Pediatric research • 2009 • Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency. PMID:19531976
• Frontiers in immunology • 2021 • Complement Genetic Variants and FH Desialylation in S. pneumoniae–Haemolytic Uraemic Syndrome. PMID:33777036

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