Table 3.
Complement pathogenic rare variants (n=6) found in six out of 108 patients with postdiarrheal HUS
| Patient | Gene | Variant | Genetic Status | No. of Patients | CFH Plasma Levela | MCP Expressiona | MAFb (%) | Demonstrated Functional Alterations | Previously Reported in STEC-HUS | Previously Reported in aHUS |
|---|---|---|---|---|---|---|---|---|---|---|
| Stx-positive patients with HUS | ||||||||||
| 1 | Complement factor H | c.2850G>T p.Gln950His | He | 1 | Normal | Normal | 0.36 | Moderately decreased binding to GAG and/or C3b (Hemolytic assay) (35) | Yes (24) | Yesc (38) |
| 2 | Thrombomodulin | c.1483C>T p.Pro495Ser | He | 1 | Normal | Normal | 0.06 | Decreased capacity to inactivate C3b (36) | No | Yes (36) |
| 3 | Complement factor H | c.1145C>A p.Ala382Glu | He | 1 | Low | Normal | Not found | Decrease FH level associated with C3 consumption (CFH deficiency)d | No | No |
| 4 | Membrane cofactor protein | c.503_504insA p.Asn170LysfsTer7 | He | 1 | Normal | Low | Not found | Decrease MCP expression (MCP deficiency)d | No | No |
| Stx-negative patients with HUS | ||||||||||
| 5 | Thrombomodulin | c.127G>A p.Ala43Thr | He | 1 | Normal | Normal | 0.34 | Decreased capacity to inactivate C3b (36) | No | Yes (36) |
| 6 | Complement factor H | c.3628C>T p.Arg1210Cyse | He | 1 | Normal | Normal | 0.017 | Alter the C3b/polyanions–binding site (37) | No | Yesc (38) |
HUS, hemolytic uremic syndrome; CFH, complement factor H; MCP, membrane cofactor protein; MAF, minor allele frequency; STEC, Shiga toxin producing E. coli; aHUS, atypical hemolytic uremic syndrome; He, heterozygous; GAG, glycosaminoglycans; FH, factor H.
a
At discharge.
b
MAF in Exome Aggregation Consortium database (http://exac.broadinstitute.org/).
c
FH aHUS mutation database (http://www.fh-hus.org/).
d
V.F.-B., personal communication.
e
Patient 6 with CFH p.Arg1210Cys pathogenic rare variant also carried a C3 variant of uncertain significance.