Identification of a New CD46 Gene Mutation Site in a Family with Atypical Hemolytic Uremic Syndrome

Background: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) caused by dysregulation of the alternative complement pathway. Mutations in key genes, including CFH, CFI, CFB, C3, and CD46, and hybrid genes generated by nonhomologous recombination between CFH and CFHR1 are known to be involved in the pathogenesis of aHUS. Among these, CD46 mutations have been reported in only a limited number of aHUS patients. Here, we present a case of aHUS associated with a rare novel homozygous mutation in the CD46 gene (c.1127+2T>A).Case presentation: We report a case of a 24-year-old Chinese male who was diagnosed with aHUS at the age of 8 and experienced six relapses over the past 16 years. Whole-exome sequencing (WES) revealed a novel mutation in the CD46 gene, specifically, a homozygous mutation at the first nucleotide of the 12th intron of the CD46 gene (NM_172359.3, c.1127+2T>A). According to the pathogenicity classification guidelines of the American College of Medical Genetics and Genomics (ACMG), this variant is classified as a pathogenic variant. To date, this variant has not been reported. Sanger sequencing confirmed the presence of the CD46 mutation. Through fluorescence quantitative PCR and enzyme-linked immunosorbent assay (ELISA) analysis, we found that the expression levels of CD46 mRNA and protein in patients' peripheral blood were significantly lower than those in healthy controls and patients' mothers.Conclusion: In our study, a novel mutation in the CD46 gene (c.1127+2T>A) was identified via WES and confirmed to affect the transcription and translation of CD46, thereby contributing to the pathogenesis of aHUS. This finding broadens the spectrum of CD46 gene variants associated with aHUS, providing a critical basis for clinical diagnosis, genetic counseling, and treatment.