AUTHOR=Piras Rossella , Valoti Elisabetta , Alberti Marta , Bresin Elena , Mele Caterina , Breno Matteo , Liguori Lucia , Donadelli Roberta , Rigoldi Miriam , Benigni Ariela , Remuzzi Giuseppe , Noris Marina 

TITLE=CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1011580

DOI=10.3389/fimmu.2022.1011580

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>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 <italic>CFH</italic> and <italic>CFHR1-5</italic> 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 <italic>CFH-CFHR</italic> genomic rearrangements in aHUS and their impact on disease onset and outcomes.</p></sec><sec><title>Methods</title><p>In this study, we report the results of <italic>CFH-CFHR</italic> 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.</p></sec><sec><title>Results</title><p>We found uncommon SVs in 8% of patients with primary aHUS: 70% carried rearrangements involving <italic>CFH</italic> alone or <italic>CFH</italic> and <italic>CFHR</italic> (group A; n=14), while 30% exhibited rearrangements including only <italic>CFHRs</italic> (group B; n=6). In group A, 6 patients presented <italic>CFH::CFHR1</italic> hybrid genes, 7 patients carried duplications in the <italic>CFH-CFHR</italic> region that resulted either in the substitution of the last <italic>CFHR1</italic> exon(s) with those of <italic>CFH</italic> (<italic>CFHR1::CFH</italic> reverse hybrid gene) or in an internal <italic>CFH</italic> 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 <italic>CFHR3<sub>1-5</sub>::CFHR4<sub>10</sub></italic> hybrid gene and one had 4 copies of <italic>CFHR1</italic> and <italic>CFHR4</italic>. 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 <italic>CFHR3<sub>1-5</sub>::CFHR4<sub>10</sub></italic> hybrid and a new internal duplication of <italic>CFH</italic>.</p></sec><sec><title>Discussion</title><p>In conclusion, these data highlight that uncommon <italic>CFH-CFHR</italic> SVs are frequent in primary aHUS and quite rare in secondary forms. Notably, genomic rearrangements involving the <italic>CFH</italic> are associated with a poor prognosis but carriers respond to anti-complement therapy.</p></sec>