TY - JOUR
T1 - Clinical characterization and identification of rare genetic variants in atypical hemolytic uremic syndrome
T2 - A Swedish retrospective observational study
AU - Åkesson, Alexander
AU - Martin, Myriam
AU - Blom, Anna M
AU - Rossing, Maria
AU - Gabrielaite, Migle
AU - Zetterberg, Eva
AU - Klintman, Jenny
N1 - © 2021 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.
PY - 2021/12
Y1 - 2021/12
N2 - 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 American College of Medical Genetics and Genomics 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. Subjects were investigated with medical record reviewing, inquiries, and laboratory analyses composed of whole genome sequencing; enzyme-linked immunosorbent assays for factor I, factor H, and factor H-specific antibodies; nephelometry for complement components three of four; flow cytometry for CD46 surface expression and immunoblotting for the presence of factor H-related protein 1. 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, 10 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). This 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.
AB - 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 American College of Medical Genetics and Genomics 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. Subjects were investigated with medical record reviewing, inquiries, and laboratory analyses composed of whole genome sequencing; enzyme-linked immunosorbent assays for factor I, factor H, and factor H-specific antibodies; nephelometry for complement components three of four; flow cytometry for CD46 surface expression and immunoblotting for the presence of factor H-related protein 1. 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, 10 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). This 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.
KW - Adult
KW - Atypical Hemolytic Uremic Syndrome/genetics
KW - Female
KW - Genetic Variation/genetics
KW - Humans
KW - Male
KW - Middle Aged
KW - Retrospective Studies
KW - Sweden
KW - Young Adult
UR - http://www.scopus.com/inward/record.url?scp=85103368996&partnerID=8YFLogxK
U2 - 10.1111/1744-9987.13634
DO - 10.1111/1744-9987.13634
M3 - Journal article
C2 - 33609329
SN - 1744-9979
VL - 25
SP - 988
EP - 1000
JO - Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy
JF - Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy
IS - 6
ER -