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

Front Immunol. 2023 Jan 30:13:1011580. doi: 10.3389/fimmu.2022.1011580. eCollection 2022.

Abstract

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 CFH and CFHR1-5 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 CFH-CFHR genomic rearrangements in aHUS and their impact on disease onset and outcomes.

Methods: In this study, we report the results of CFH-CFHR 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 CFH alone or CFH and CFHR (group A; n=14), while 30% exhibited rearrangements including only CFHRs (group B; n=6). In group A, 6 patients presented CFH::CFHR1 hybrid genes, 7 patients carried duplications in the CFH-CFHR region that resulted either in the substitution of the last CFHR1 exon(s) with those of CFH (CFHR1::CFH reverse hybrid gene) or in an internal CFH 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 CFHR31-5::CFHR410 hybrid gene and one had 4 copies of CFHR1 and CFHR4. 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 CFHR31-5::CFHR410 hybrid and a new internal duplication of CFH.

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

Keywords: atypical hemolytic uremic syndrome (aHUS); complement; copy number variations (CNVs); eculizumab; factor H (FH); factor H-related proteins (FHRs); single molecule real-time (SMRT); structural variants (SVs).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atypical Hemolytic Uremic Syndrome* / drug therapy
  • Atypical Hemolytic Uremic Syndrome* / epidemiology
  • Atypical Hemolytic Uremic Syndrome* / genetics
  • Complement Factor H / genetics
  • DNA Copy Number Variations
  • Genomics
  • Humans
  • Neoplasm Recurrence, Local
  • Prevalence

Substances

  • Complement Factor H

Grants and funding

This work was partially supported by Kidneeds Foundation (Kidneeds projects 735/8215 and 698/7603) and by UNEARTH project (project ID 1745126). We would also like to thank Associazione Nazionale Anziani Pensionati di Confartigianato Imprese Bergamo for its support. RP, EV, MB and MR are recipients of a research contract from Progetto DDD Onlus-Associazione per la lotta alla DDD (Milan, Italy). CM is recipient of a grant from Fondazione Regionale per la Ricerca Biomedica (FRRB; UNEARTH project 1745126). LL is recipient of a fellowship from Fondazione Aiuti per la Ricerca sulle Malattie Rare ARMR ONLUS (Bergamo, Italy). The funding sources had no role in study design, nor in the collection, analysis or interpretation of data, nor in the writing of the report or in the decision to submit the paper for publication.