and structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome.

INTRODUCTION

Atypical hemolytic uremic syndrome (aHUS) is a rare disease that manifests with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, and is associated with dysregulation of the alternative complement pathway. The chromosomal region including and is rich in repeated sequences, favoring genomic rearrangements that have been reported in several patients with aHUS. However, there are limited data on the prevalence of uncommon genomic rearrangements in aHUS and their impact on disease onset and outcomes.

METHODS

In this study, we report the results of Copy Number Variation (CNV) analysis and the characterization of resulting structural variants (SVs) in a large cohort of patients, including 258 patients with primary aHUS and 92 with secondary forms.

RESULTS

We found uncommon SVs in 8% of patients with primary aHUS: 70% carried rearrangements involving alone or and (group A; n=14), while 30% exhibited rearrangements including only (group B; n=6). In group A, 6 patients presented hybrid genes, 7 patients carried duplications in the region that resulted either in the substitution of the last exon(s) with those of ( reverse hybrid gene) or in an internal duplication. In group A, the large majority of aHUS acute episodes not treated with eculizumab (12/13) resulted in chronic ESRD; in contrast, anti-complement therapy induced remission in 4/4 acute episodes. aHUS relapse occurred in 6/7 grafts without eculizumab prophylaxis and in 0/3 grafts with eculizumab prophylaxis. In group B, 5 subjects had the hybrid gene and one had 4 copies of and . Compared with group A, patients in group B exhibited a higher prevalence of additional complement abnormalities and earlier disease onset. However, 4/6 patients in this group underwent complete remission without eculizumab treatment. In secondary forms we identified uncommon SVs in 2 out of 92 patients: the hybrid and a new internal duplication of .

DISCUSSION

In conclusion, these data highlight that uncommon SVs are frequent in primary aHUS and quite rare in secondary forms. Notably, genomic rearrangements involving the are associated with a poor prognosis but carriers respond to anti-complement therapy.