{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T04:10:32Z","timestamp":1792296632042,"version":"4.4.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T00:00:00Z","timestamp":1675036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100022720","name":"Fondazione Regionale per la Ricerca Biomedica","doi-asserted-by":"publisher","award":["1745126"],"award-info":[{"award-number":["1745126"]}],"id":[{"id":"10.13039\/501100022720","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010281","name":"Kidneeds","doi-asserted-by":"publisher","award":["735\/8215, 698\/7603"],"award-info":[{"award-number":["735\/8215, 698\/7603"]}],"id":[{"id":"10.13039\/100010281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats: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 <jats:italic>CFH<\/jats:italic> and <jats:italic>CFHR1-5<\/jats: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 <jats:italic>CFH-CFHR<\/jats:italic> genomic rearrangements in aHUS and their impact on disease onset and outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we report the results of <jats:italic>CFH-CFHR<\/jats: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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found uncommon SVs in 8% of patients with primary aHUS: 70% carried rearrangements involving <jats:italic>CFH<\/jats:italic> alone or <jats:italic>CFH<\/jats:italic> and <jats:italic>CFHR<\/jats:italic> (group A; n=14), while 30% exhibited rearrangements including only <jats:italic>CFHRs<\/jats:italic> (group B; n=6). In group A, 6 patients presented <jats:italic>CFH::CFHR1<\/jats:italic> hybrid genes, 7 patients carried duplications in the <jats:italic>CFH-CFHR<\/jats:italic> region that resulted either in the substitution of the last <jats:italic>CFHR1<\/jats:italic> exon(s) with those of <jats:italic>CFH<\/jats:italic> (<jats:italic>CFHR1::CFH<\/jats:italic> reverse hybrid gene) or in an internal <jats:italic>CFH<\/jats: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 <jats:italic>CFHR3<jats:sub>1-5<\/jats:sub>::CFHR4<jats:sub>10<\/jats:sub><\/jats:italic> hybrid gene and one had 4 copies of <jats:italic>CFHR1<\/jats:italic> and <jats:italic>CFHR4<\/jats: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 <jats:italic>CFHR3<jats:sub>1-5<\/jats:sub>::CFHR4<jats:sub>10<\/jats:sub><\/jats:italic> hybrid and a new internal duplication of <jats:italic>CFH<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In conclusion, these data highlight that uncommon <jats:italic>CFH-CFHR<\/jats:italic> SVs are frequent in primary aHUS and quite rare in secondary forms. Notably, genomic rearrangements involving the <jats:italic>CFH<\/jats:italic> are associated with a poor prognosis but carriers respond to anti-complement therapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1011580","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T09:09:36Z","timestamp":1675069776000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome"],"prefix":"10.3389","volume":"13","author":[{"given":"Rossella","family":"Piras","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Valoti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Alberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Bresin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Mele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Breno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Liguori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Donadelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Rigoldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariela","family":"Benigni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Remuzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Noris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2004100861","article-title":"Hemolytic uremic syndrome","volume":"16","author":"Noris","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.02210310","article-title":"Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype","volume":"5","author":"Noris","year":"2010","journal-title":"Clin J Am Soc Nephrol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00853","article-title":"Rare functional variants in complement genes and anti-FH autoantibodies-associated aHUS","volume":"10","author":"Valoti","year":"2019","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.10.005","article-title":"Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a \"Kidney disease: Improving global outcomes\" (KDIGO) controversies conference","volume":"91","author":"Goodship","year":"2017","journal-title":"Kidney Int"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfw453","article-title":"Eculizumab in secondary atypical haemolytic uraemic syndrome","volume":"32","author":"Cavero","year":"2017","journal-title":"Nephrol Dial Transplant"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s002510050534","article-title":"A radiation hybrid map of complement factor h and factor h-related genes","volume":"49","author":"Diaz-Guillen","year":"1999","journal-title":"Immunogenetics"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.04.008","article-title":"Factor h-related proteins determine complement-activating surfaces","volume":"36","author":"Jozsi","year":"2015","journal-title":"Trends Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2008.04.008","article-title":"Factor h family proteins and human diseases","volume":"29","author":"Jozsi","year":"2008","journal-title":"Trends Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"I9","DOI":"10.1016\/j.vaccine.2008.11.021","article-title":"Complement factor h related proteins in immune diseases","volume":"26","author":"Skerka","year":"2008","journal-title":"Vaccine"},{"key":"B10","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0162-3109(99)00015-6","article-title":"The factor h protein family","volume":"42","author":"Zipfel","year":"1999","journal-title":"Immunopharmacology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13166","article-title":"The factor h protein family: The switchers of the complement alternative pathway","author":"Lucientes-Continente","year":"2022","journal-title":"Immunol Rev"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1219260110","article-title":"Dimerization of complement factor h-related proteins modulates complement activation in vivo","volume":"110","author":"Goicoechea de Jorge","year":"2013","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68280","article-title":"C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation","volume":"123","author":"Tortajada","year":"2013","journal-title":"J Clin Invest"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01328","article-title":"Factor h-related (FHR)-1 and FHR-2 form homo- and heterodimers, while FHR-5 circulates only as homodimer in human plasma","volume":"8","author":"van Beek","year":"2017","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2013.06.001","article-title":"Complement factor h related proteins (CFHRs)","volume":"56","author":"Skerka","year":"2013","journal-title":"Mol Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2019050515","article-title":"CFHR gene variations provide insights in the pathogenesis of the kidney diseases atypical hemolytic uremic syndrome and C3 glomerulopathy","volume":"31","author":"Zipfel","year":"2020","journal-title":"J Am Soc Nephrol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.670727","article-title":"CFH and CFHR copy number variations in C3 glomerulopathy and immune complex-mediated membranoproliferative glomerulonephritis","volume":"12","author":"Piras","year":"2021","journal-title":"Front Genet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-05-221549","article-title":"Association of factor h autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome","volume":"115","author":"Moore","year":"2010","journal-title":"Blood"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.579418","article-title":"Molecular studies and an ex vivo complement assay on endothelium highlight the genetic complexity of atypical hemolytic uremic syndrome: The case of a pedigree with a null CD46 variant","volume":"7","author":"Piras","year":"2020","journal-title":"Front Med (Lausanne)"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2590","article-title":"Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome","volume":"45","author":"Lemaire","year":"2013","journal-title":"Nat Genet"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.08520814","article-title":"Characterization of a new DGKE intronic mutation in genetically unsolved cases of familial atypical hemolytic uremic syndrome","volume":"10","author":"Mele","year":"2015","journal-title":"Clin J Am Soc Nephrol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg363","article-title":"Complement factor h mutations and gene polymorphisms in haemolytic uraemic syndrome: the c-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease","volume":"12","author":"Caprioli","year":"2003","journal-title":"Hum Mol Genet"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi066","article-title":"Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32","volume":"14","author":"Esparza-Gordillo","year":"2005","journal-title":"Hum Mol Genet"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.030783","article-title":"The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor h and membrane cofactor protein: evidence from two independent cohorts","volume":"42","author":"Fremeaux-Bacchi","year":"2005","journal-title":"J Med Genet"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2015.06.021","article-title":"FHR-3 and FHR-1 variants associate in an extended haplotype conferring increased risk of atypical hemolytic uremic syndrome","volume":"67","author":"Bernabeu-Herrero","year":"2015","journal-title":"Mol Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2012090884","article-title":"Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype","volume":"24","author":"Bresin","year":"2013","journal-title":"J Am Soc Nephrol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013121339","article-title":"A novel atypical hemolytic uremic syndrome-associated hybrid CFHR1\/CFH gene encoding a fusion protein that antagonizes factor h-dependent complement regulation","volume":"26","author":"Valoti","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1159\/000497823","article-title":"Hemolytic uremic syndrome in an infant with primary hyperoxaluria type II: An unreported clinical association","volume":"142","author":"Valoti","year":"2019","journal-title":"Nephron"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030431","article-title":"Atypical haemolytic uraemic syndrome associated with a hybrid complement gene","volume":"3","author":"Venables","year":"2006","journal-title":"PloS Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfq658","article-title":"A novel deletion in the RCA gene cluster causes atypical hemolytic uremic syndrome","volume":"26","author":"Maga","year":"2011","journal-title":"Nephrol Dial Transplant"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/ng0710-553","article-title":"Associations of CFHR1-CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent","volume":"42","author":"Raychaudhuri","year":"2010","journal-title":"Nat Genet"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-013-2560-2","article-title":"A novel hybrid CFHR1\/CFH gene causes atypical hemolytic uremic syndrome","volume":"28","author":"Eyler","year":"2013","journal-title":"Pediatr Nephrol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9408","article-title":"De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor h associated with atypical hemolytic uremic syndrome","volume":"27","author":"Heinen","year":"2006","journal-title":"Hum Mutat"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2193","article-title":"Gene conversion: mechanisms, evolution and human disease","volume":"8","author":"Chen","year":"2007","journal-title":"Nat Rev Genet"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020010069","article-title":"Molecular bases for the association of FHR-1 with atypical hemolytic uremic syndrome and other diseases","volume":"137","author":"Martin Merinero","year":"2021","journal-title":"Blood"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.615748","article-title":"Deregulation of factor h by factor h-related protein 1 depends on sialylation of host surfaces","volume":"12","author":"Dopler","year":"2021","journal-title":"Front Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2017050518","article-title":"Factor h competitor generated by gene conversion events associates with atypical hemolytic uremic syndrome","volume":"29","author":"Goicoechea de Jorge","year":"2018","journal-title":"J Am Soc Nephrol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20367","article-title":"Duplications in the DMD gene","volume":"27","author":"White","year":"2006","journal-title":"Hum Mutat"},{"key":"B39","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/humu.1380010103","article-title":"Partial gene duplication as a cause of human disease","volume":"1","author":"Hu","year":"1992","journal-title":"Hum Mutat"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201465","article-title":"Deletion and duplication screening in the DMD gene using MLPA","volume":"13","author":"Lalic","year":"2005","journal-title":"Eur J Hum Genet"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020006931","article-title":"The familial risk of developing atypical hemolytic uremic syndrome","author":"Arjona","year":"2020","journal-title":"Blood"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-10-007252","article-title":"Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome","volume":"108","author":"Caprioli","year":"2006","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1086\/344515","article-title":"Structural and functional characterization of factor h mutations associated with atypical hemolytic uremic syndrome","volume":"71","author":"Sanchez-Corral","year":"2002","journal-title":"Am J Hum Genet"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015050580","article-title":"Molecular basis of factor h R1210C association with ocular and renal diseases","volume":"27","author":"Recalde","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15171","article-title":"The role of complement in arterial hypertension and hypertensive end organ damage","volume":"178","author":"Wenzel","year":"2021","journal-title":"Br J Pharmacol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jhh.1001051","article-title":"Hypertension and the prothrombotic state","volume":"14","author":"Lip","year":"2000","journal-title":"J Hum Hypertens"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2019040331","article-title":"Use of highly individualized complement blockade has revolutionized clinical outcomes after kidney transplantation and renal epidemiology of atypical hemolytic uremic syndrome","volume":"30","author":"Zuber","year":"2019","journal-title":"J Am Soc Nephrol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.transproceed.2019.10.015","article-title":"Atypical hemolytic uremic syndrome after kidney transplantation: Lessons learned from the good, the bad, and the ugly","volume":"52","author":"Fayek","year":"2020","journal-title":"A Case Ser With Lit Review Transplant Proc"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1011580\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T09:09:40Z","timestamp":1675069780000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1011580\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,30]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2022.1011580"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1011580","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,30]]},"article-number":"1011580"}}