Unveiling (epi)genetic variants for Atypical Hemolytic Uremic Syndrome (aHUS) beyond current knowledge: idiopathic cases, familial occurrence and auto-antibody development

Atypical hemolytic uremic syndrome (aHUS) is a rare and severe disease characterized by renal and multi-organ damage. It is mainly caused by pathogenic variants in complement system factors or in complement regulating genes. Among genetic causes, CFHR3 and CFHR1 (R3-R1) homozygous deletions have been reported in some patients in association with factor H autoantibodies (FHAAs), but its contribution in the development of aHUS is not well elucidated. In addition, several cases without a molecular diagnosis have been described probably due to a genetic predisposition not yet identified. In our pilot study, given the genomic complexity in which R3-R1 genes are located, we plan to recruit families with at least one patient bearing the homozygous R3-R1 deletion combined with FHAAs (10 cases) and not (10 cases) that will be analyzed using a long-read whole genome sequencing. This approach based on DNA passage through a nanopore, will unveil complex and repetitive genomic regions obtaining also information about the native methylation status and potential epigenetic changes. In detail, any differences in their rearrangement or in their (epi)genome that could explain a diverse immune reaction will be evaluated in the two groups. The unaffected relatives and discordant siblings bearing the homozygous R3-R1 deletion will be also studied to identify (epi)genetic discrepancies with affected relatives. This study will help to clarify the contribution of R3-R1 deletion in association to FHAAs and to unveil the protective or predisposing genetic factors at the basis of healthy carriers and aHUS patients, respectively.