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 resulting from the dysregulation of the alternative complement pathway. Pathogenic variants in complement regulators (e.g., CFH, CFI, CD46, THBD), effectors (C3, CFB), CFHR genes, and non-complement genes (e.g., DGKE, INF2), as well as anti-factor H autoantibodies, play significant roles in disease pathogenesis. Furthermore, numerous CFH-CFHR hybrid genes are increasingly recognized as significant contributors to aHUS pathogenesis. Among these, epidemiological data on CD46-associated aHUS remain limited. 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 present a case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. Whole-exome sequencing (WES) revealed a novel homozygous mutation in the CD46 gene (c.1127 + 2T > A; intron 12 splice site), which is classified as pathogenic according to ACMG guidelines and has not been previously reported. Sanger sequencing confirmed the presence of this variant. Further analyses demonstrated significantly reduced CD46 mRNA and protein expression in the patient's peripheral blood compared to healthy controls and his mother, as assessed by qPCR and ELISA.

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.