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Clinical characterization and identification of rare genetic variants in atypical hemolytic uremic syndrome : a Swedish retrospective observational study

Åkesson, Alexander LU ; Martin, Myriam LU ; Blom, Anna M LU orcid ; Rossing, Maria ; Gabrielaite, Migle ; Zetterberg, Eva LU and Klintman, Jenny LU (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.

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author
; ; ; ; ; and
organization
publishing date
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
  • scopus:85103368996
  • pmid:33609329
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
2025-10-14 09:57:06
@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&gt;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}},
}