Clinical characterization and identification of rare genetic variants in atypical hemolytic uremic syndrome: a Swedish retrospective observational study

Abstract Complement‐mediated atypical hemolytic uremic syndrome (aHUS) is an ultra‐rare renal disease primarily caused by genetic alterations in complement proteins. The genetic work‐up required for confirmation of diagnosis is complicated and not always logistically accessible. The aim of the present study was to apply a diagnostic scheme compliant with the American College of Medical Genetics and Genomics guidelines to investigate the prevalence of complement‐mediated aHUS among subjects formerly included in a retrospective cohort of clinically suspected aHUS. Clinical outcomes and genetic correlations to complement analyses were assessed. Subjects were investigated with medical record reviewing, inquiries, and laboratory analyses composed of whole genome sequencing; enzyme‐linked immunosorbent assays for factor I, factor H, and factor H‐specific antibodies; nephelometry for complement components three of four; flow cytometry for CD46 surface expression and immunoblotting for the presence of factor H‐related protein 1. In total, 45% ( n = 60/134) of the subjects were deceased at the time of study. Twenty of the eligible subjects consented to study participation. Based on genetic sequencing and clinical characteristics, six were categorized as definite/highly suspected complement‐mediated aHUS, 10 as non‐complement‐mediated aHUS and four as having an HUS‐like phenotype. In the complement‐mediated aHUS group, two subjects had not received an aHUS diagnosis during the routine clinical management. Disease‐contributing/likely disease‐contributing genetic variants were identified in five subjects, including a novel missense variant in the complement factor H gene (c.3450A>G, p.I1150M). This study illustrates the risk for misdiagnosis in the management of patients with complement‐mediated aHUS and the importance of a comprehensive assessment of both phenotype and genotype to reach a diagnosis.