Comprehensive genetic analysis and genotype-phenotype correlations in pediatric patients with atypical hemolytic...

Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by the dysregulation of the alternative pathway. The objective of this study was to evaluate the genetic background and genotype-phenotype correlations in pediatric patients with aHUS.

This retrospective study enrolled 116 pediatric patients from 2013 to 2023 in China. Here, we screened rare and common variants of atypical hemolytic uremic syndrome predisposing genes, as well as reported the clinical characteristics and extrarenal manifestations.

Genetic mutations were identified in 20% of patients. Factor H autoantibodies were detected in 53% of patients, with a homozygous CFHR1 deletion observed in 50% of them. The variant of CFHR5 p.V170M (7% vs. 0, P = 0.009, adjusted P-value = 0.036) was enriched in aHUS patients. No significant difference in the frequencies of CFH-H3 and CD46ggaac at-risk haplotypes was observed between aHUS patients and healthy controls. CFH was the most common mutation and was associated with the poorest prognosis, with a 1-year kidney survival rate of 45% after disease onset in the absence of complement blockade. Among patients with factor H autoantibodies, those with a homozygous CFHR1 deletion exhibited a significantly higher relapse rate.

Chinese children with aHUS present a low proportion of genetic mutations. Kidney outcomes significantly differ according to genetic backgrounds in the pre-complement blockade era. Homozygous CFHR1 homozygous deletion increases the risk of relapse in patients with factor H autoantibodies.