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CFH and CFHR 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 CFH and CFHR1-5 is...

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Autores principales: Piras, Rossella, Valoti, Elisabetta, Alberti, Marta, Bresin, Elena, Mele, Caterina, Breno, Matteo, Liguori, Lucia, Donadelli, Roberta, Rigoldi, Miriam, Benigni, Ariela, Remuzzi, Giuseppe, Noris, Marina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9923232/
https://www.ncbi.nlm.nih.gov/pubmed/36793547
http://dx.doi.org/10.3389/fimmu.2022.1011580
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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
author_facet Piras, Rossella
Valoti, Elisabetta
Alberti, Marta
Bresin, Elena
Mele, Caterina
Breno, Matteo
Liguori, Lucia
Donadelli, Roberta
Rigoldi, Miriam
Benigni, Ariela
Remuzzi, Giuseppe
Noris, Marina
author_sort Piras, Rossella
collection PubMed
description 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 CFHR3(1-5)::CFHR4(10) 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 CFHR3(1-5)::CFHR4(10) 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.
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spelling pubmed-99232322023-02-14 CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome Piras, Rossella Valoti, Elisabetta Alberti, Marta Bresin, Elena Mele, Caterina Breno, Matteo Liguori, Lucia Donadelli, Roberta Rigoldi, Miriam Benigni, Ariela Remuzzi, Giuseppe Noris, Marina Front Immunol Immunology 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 CFHR3(1-5)::CFHR4(10) 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 CFHR3(1-5)::CFHR4(10) 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. Frontiers Media S.A. 2023-01-30 /pmc/articles/PMC9923232/ /pubmed/36793547 http://dx.doi.org/10.3389/fimmu.2022.1011580 Text en Copyright © 2023 Piras, Valoti, Alberti, Bresin, Mele, Breno, Liguori, Donadelli, Rigoldi, Benigni, Remuzzi and Noris https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Piras, Rossella
Valoti, Elisabetta
Alberti, Marta
Bresin, Elena
Mele, Caterina
Breno, Matteo
Liguori, Lucia
Donadelli, Roberta
Rigoldi, Miriam
Benigni, Ariela
Remuzzi, Giuseppe
Noris, Marina
CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome
title CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome
title_full CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome
title_fullStr CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome
title_full_unstemmed CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome
title_short CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome
title_sort cfh and cfhr structural variants in atypical hemolytic uremic syndrome: prevalence, genomic characterization and impact on outcome
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9923232/
https://www.ncbi.nlm.nih.gov/pubmed/36793547
http://dx.doi.org/10.3389/fimmu.2022.1011580
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