Clinical characterization and identification of rare genetic variants in atypical hemolytic uremic syndrome : a Swedish retrospective observational study
(2021) In Therapeutic Apheresis and Dialysis 25(6). p.988-1000- Abstract
INTRODUCTION: Complement-mediated atypical hemolytic uremic syndrome (aHUS) is an ultra-rare renal disease primarily caused by genetic alterations in complement proteins. The genetic work-up required for confirmation of diagnosis is complicated and not always logistically accessible. The aim of the present study was to apply a diagnostic scheme compliant with the ACMG guidelines to investigate the prevalence of complement-mediated aHUS among subjects formerly included in a retrospective cohort of clinically suspected aHUS. Clinical outcomes and genetic correlations to complement analyses were assessed.
METHODS: Subjects were investigated with medical record reviewing, inquiries and laboratory analyses composed of whole genome... (More)
INTRODUCTION: Complement-mediated atypical hemolytic uremic syndrome (aHUS) is an ultra-rare renal disease primarily caused by genetic alterations in complement proteins. The genetic work-up required for confirmation of diagnosis is complicated and not always logistically accessible. The aim of the present study was to apply a diagnostic scheme compliant with the ACMG guidelines to investigate the prevalence of complement-mediated aHUS among subjects formerly included in a retrospective cohort of clinically suspected aHUS. Clinical outcomes and genetic correlations to complement analyses were assessed.
METHODS: Subjects were investigated with medical record reviewing, inquiries and laboratory analyses composed of whole genome sequencing; ELISA for factor I, factor H and factor H-specific antibodies; nephelometry for complement components 3/4; flow cytometry for CD46 surface expression and immunoblotting for the presence of factor H-related protein 1.
RESULTS: In total, 45% (n=60/134) of the subjects were deceased at the time of study. Twenty of the eligible subjects consented to study participation. Based on genetic sequencing and clinical characteristics, six were categorized as definite/highly suspected complement-mediated aHUS, ten as non-complement-mediated aHUS and four as having an HUS-like phenotype. In the complement-mediated aHUS group, two subjects had not received an aHUS diagnosis during the routine clinical management. Disease-contributing/likely disease-contributing genetic variants were identified in five subjects, including a novel missense variant in the complement factor H gene (c.3450A>G,p.I1150M).
CONCLUSION: The study illustrates the risk for misdiagnosis in the management of patients with complement-mediated aHUS and the importance of a comprehensive assessment of both phenotype and genotype to reach a diagnosis. This article is protected by copyright. All rights reserved.
(Less)
- author
- Åkesson, Alexander LU ; Martin, Myriam LU ; Blom, Anna M LU ; Rossing, Maria ; Gabrielaite, Migle ; Zetterberg, Eva LU and Klintman, Jenny LU
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Therapeutic Apheresis and Dialysis
- volume
- 25
- issue
- 6
- pages
- 988 - 1000
- publisher
- Wiley-Blackwell
- external identifiers
-
- pmid:33609329
- scopus:85103368996
- ISSN
- 1744-9979
- DOI
- 10.1111/1744-9987.13634
- language
- English
- LU publication?
- yes
- id
- 6e2b2941-81e4-46f4-972c-448d3af1cea2
- date added to LUP
- 2021-03-24 14:50:08
- date last changed
- 2024-09-19 18:43:31
@article{6e2b2941-81e4-46f4-972c-448d3af1cea2, abstract = {{<p>INTRODUCTION: Complement-mediated atypical hemolytic uremic syndrome (aHUS) is an ultra-rare renal disease primarily caused by genetic alterations in complement proteins. The genetic work-up required for confirmation of diagnosis is complicated and not always logistically accessible. The aim of the present study was to apply a diagnostic scheme compliant with the ACMG guidelines to investigate the prevalence of complement-mediated aHUS among subjects formerly included in a retrospective cohort of clinically suspected aHUS. Clinical outcomes and genetic correlations to complement analyses were assessed.</p><p>METHODS: Subjects were investigated with medical record reviewing, inquiries and laboratory analyses composed of whole genome sequencing; ELISA for factor I, factor H and factor H-specific antibodies; nephelometry for complement components 3/4; flow cytometry for CD46 surface expression and immunoblotting for the presence of factor H-related protein 1.</p><p>RESULTS: In total, 45% (n=60/134) of the subjects were deceased at the time of study. Twenty of the eligible subjects consented to study participation. Based on genetic sequencing and clinical characteristics, six were categorized as definite/highly suspected complement-mediated aHUS, ten as non-complement-mediated aHUS and four as having an HUS-like phenotype. In the complement-mediated aHUS group, two subjects had not received an aHUS diagnosis during the routine clinical management. Disease-contributing/likely disease-contributing genetic variants were identified in five subjects, including a novel missense variant in the complement factor H gene (c.3450A>G,p.I1150M).</p><p>CONCLUSION: The study illustrates the risk for misdiagnosis in the management of patients with complement-mediated aHUS and the importance of a comprehensive assessment of both phenotype and genotype to reach a diagnosis. This article is protected by copyright. All rights reserved.</p>}}, author = {{Åkesson, Alexander and Martin, Myriam and Blom, Anna M and Rossing, Maria and Gabrielaite, Migle and Zetterberg, Eva and Klintman, Jenny}}, issn = {{1744-9979}}, language = {{eng}}, number = {{6}}, pages = {{988--1000}}, publisher = {{Wiley-Blackwell}}, series = {{Therapeutic Apheresis and Dialysis}}, title = {{Clinical characterization and identification of rare genetic variants in atypical hemolytic uremic syndrome : a Swedish retrospective observational study}}, url = {{http://dx.doi.org/10.1111/1744-9987.13634}}, doi = {{10.1111/1744-9987.13634}}, volume = {{25}}, year = {{2021}}, }