Table 1.

Molecular Genetic Testing Used in Atypical Hemolytic-Uremic Syndrome

Gene 1Proportion of Genetic aHUS Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detected by Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
C3 6% 5, 6100%None reported 7
CD46 10% 5, 6, 8100%None reported 7
CFB 2% 6100%None reported 7
CFH 21%-25% 5, 6~95%-97%~3%-5% 9
CFH/CFHR1 hybrid allele~3%-5% 9NA100%
CFHR1/CFH hybrid allele3 individuals 10NA100%
CFHR1/CFHR4 deletion3 individuals 11NA100%
CFHR3/CFHR1 deletion26.5% 11NA100%
CFHR5 6 individuals 12100%None reported 7
CFI 6% 5, 6100%None reported 7
DGKE 3% 6, 13100%None reported 7
THBD 2%-5% 6, 14100%None reported 7
VTN 8 individuals 6100%None reported 7
Unknown~40%NA
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.

Bu et al [2018]

7.

No large deletions or duplications involving C3, CD46, CFB, CFHR5, CFI, DGKE, THBD, or VTN have been reported to cause aHUS. Data are derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017].

8.

In one child, complete paternal uniparental isodisomy of chromosome 1 with homozygosity for a splice defect of exon 10 resulted in severe deficiency of CD46 expression [Frémeaux-Bacchi et al 2007].

9.

Several CFH/CFHR1 hybrid alleles have been identified (see Molecular Genetics). Sequence analysis does not detect the CFH/CFHR1 hybrid allele that accounts for approximately 3%-5% of all aHUS [Venables et al 2006]. Other methods including MLPA analysis may be used to detect the hybrid gene [Venables et al 2006, Maga et al 2011].

10.

Two CFHR1/CFH hybrid alleles have been identified by MLPA [Eyler et al 2013, Valoti et al 2015].

11.

CFHR3/CFHR1 deletion is often associated with the formation of anti-factor H autoantibodies causing autoimmune aHUS [Zipfel et al 2020].

12.
13.

DGKE pathogenic variants are found in approximately 27% of individuals presenting with aHUS before age 1 year [Lemaire et al 2013].

14.

From: Genetic Atypical Hemolytic-Uremic Syndrome

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