Atypical hemolytic uremic syndrome in children : investigation of the molecular genetic and immunological causes with comprehensive analysis of clinical findings

다국어 초록 (Multilingual Abstract)

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a genetic predisposition. We studied a Korean pediatric cohort to delineate the various etiologies and clinical characteristics.
Methods: A multicenter cohort of 51 Korean children with aHUS was screened for mutations by targeted exome sequencing covering 46 complement related genes. Anti-complement-factor-H autoantibodies (anti-CFH) titers were measured. Multiplex ligation dependent probe amplification assay was performed to detect deletions in the complement factor-H related protein (CFHR) genes. We grouped the patients according to the etiology and compared the clinical features using the Mann-Whitney U test and chi-square test.
Results: Fifteen patients (Group A, 29.7%) had anti-CFH and mutations were detected in 11 (Group B, 21.6%) patients, including one with combined mutations. The remaining 25 (Group C, 49.0%) were neither–positive. Anti-CFH-association was more frequent than the world-wide prevalence. Group A showed older onset age than Group B. Group B showed worst renal outcome. Gene frequencies of homozygous CFHR1 deletion were 73.3%, 2.7% and 1% in Group A, Group B+C and the control, respectively.
Conclusions: In our cohort, we observed a relatively high incidence of anti-CFH-association. Clinical outcomes largely conformed to the previous reports. Although the size is limited, this cohort provides a reassessment of clinicogenetic features of aHUS in Korean children.

목차 (Table of Contents)

• Table of Contents
• Abstract •••••••••••••••••• i
• Table of Contents ••••••••• iii
• List of Tables ••••••••••••• iv
• List of Figures ••••••••••••• v
• Introduction ••••••••••••••• 1
• Materials and Methods •••• 3
• Results ••••••••••••••••••• 7
• Discussion ••••••••••••••• 20
• References ••••••••••••••• 25
• Supplementary data ••••••• 33
• 국 문 초 록 •••••••••••••••• 38
• List of Tables
• Table 1. Mutational analyses ••••• 10
• Table 2. Clinical presentation and laboratory findings in acute aHUS ••••••••••••••••••••• 11
• Table 3. Treatment and prognosis (follow-up > 3 months) •••••••••••••••••••••••• 13
• Table 4. MLPA CFHR1 and CFHR3 genotype analysis •••••••••••••••••••••••• 14
• Table 5. Comparison with other cohorts ••••••••••••••••••••••••• 16
• Supplemental Table 1. List of 46 genes included in the targeted exome sequencing •••••• 33
• Supplemental Table 2. Other genetic variations detected by targeted exome sequencing and in silico tools for prediction ••••••••••••••••••••••• 35
• Supplemental Table 3. In silico tools for functional prediction of the genetic variations •••••••••••••••••••••••• 37 
• List of Figures
• Figure 1. Etiology of atypical hemolytic uremic syndrome ••••••••••••••••••••• 17
• Figure 2. Age of onset of atypical hemolytic uremic syndrome ••••••••••••••••••••• 18
• Figure 3. CFHR1 and CFHR3 genotyping in atypical hemolytic uremic syndrome patients using multiplex ligation-dependent probe amplification assay ••••••••••••••••••••••••• 19