Table 2.
Summary of genetic or acquired complement abnormalities identified in 21 patients with atypical hemolytic uremic syndrome who discontinued eculizumab
| Pt | Gene/Ab | Pathogenic Variant | Het/Hom | Comments | MAF, % | PolyPhen-2 Scorea | Previously Reported in aHUS | Variant Classification | Relapse (mo after Discontinuation) |
|---|---|---|---|---|---|---|---|---|---|
| 1 | CFH | Large deletion in exon 1 | Het | Large deletion leading to quantitative FH deficiency | Novel | Codon stop gained | No | Pathogenic | 6 |
| 2 | CFH | c.3572 C>G; p.Ser1191Trp | Het | Variant located in exon coding for SCR20 of FH, leading to functional deficiency | Novel | Probably damaging (0.999) | Yes | Pathogenic | 10 |
| 3 | CFH | c.773 C>T; p.Pro258Leu | Het | Variant located in exon coding for SCR; FH and C3 levels in the normal range | 0.00083 | Probably damaging (0.999) | Yes | Likely pathogenic | 22 |
| 4 | CFH | c.3048 C>A; p.Tyr1016a | Hom | Variant located in exon coding for SCR17, leading to complete FH deficiency | 0.0008239 | Codon stop gained | No | Pathogenic | 6 |
| 5 | CFH | c.3572C>T; p. Ser1191Leu | Het | Mutation located in exon coding for SCR20, leading to FH functional deficiency | Novel | Benign (0.151) | Yes (rs460897) | Pathogenic | 21 |
| 6 | CFH | c.3628C>T; p.Arg1210Cys | Het | Variant located in exon coding for SCR20, leading to FH functional deficiency | 0.01730 (rs121913059) | Benign (0.024) | Yes | Pathogenic | |
| 7 | CFH | c.1789T>C; p.Cys597Arg | Het | Variant located in exon coding for SCR10, leading to quantitative FH deficiency | Novel | Probably damaging (1) | No | Pathogenic | 3 |
| 8 | CFH | c.3557 A>C; p.Lys1186Thr | Het | Variant located in exon coding for SCR20 | Novel | Possibly damaging (0.953) | No | Likely pathogenic | |
| 9 | CFH | c.1868 G>C; p.Cys623Ser | Het | Associated with quantitative FH deficiency | Novel | Probably damaging (1) | Yes | Pathogenic | 7 |
| 10 | CFH | c.245A>G p.Lys82Arg | Het | Variant located in exon coding for SCR2; FH and C3 levels are in the normal range | 0.001649 (rs376337060) | Benign (0.425) | No | Likely pathogenic | |
| 11 | CFH-CFHR1 hybrid gene | CFH-CFHR1 hybrid gene | Het | Complex rearrangement, leading to functional FH deficiency | Novel | Yes | Pathogenic | 3 | |
| 12 | MCP | c.286+1 G>C | Het | Heterozygous MCP deficiency (low MCP expression on granulocytes) | Novel | Splice region | Yes | Pathogenic | 15 |
| 13 | MCP | c.608 T>C; p.Ile203Thr | Het | MCP expression in the normal range; functional consequences unknown | Novel | No | VUS | ||
| 14 | MCP | c.286+1 G>C | Het | Complete MCP deficiency (low MCP expression on granulocytes) | Novel | Splice region | Yes | Pathogenic | |
| 15 | MCP | c.287–2 A>G | Het | Heterozygous MCP deficiency (low MCP expression on granulocytes) | 0.003121 | Splice region | Yes | Pathogenic | 29 |
| 16 | MCP | c.175C>T; p.Arg59a | Het | Heterozygous MCP deficiency (low MCP expression on granulocytes) | Novel | Stop gained | Yes | Pathogenic | |
| 17 | MCP | c.175C>T; p.Arg59a | Het | Heterozygous MCP deficiency (low MCP expression on granulocytes) | Novel | Stop gained | Yes | Pathogenic | |
| 18 | MCP | c.175C>T; p.Arg59a | Het | Heterozygous MCP deficiency (low MCP expression on granulocytes) | Novel | Stop gained | Yes | Pathogenic | |
| 19 | MCP | c.350delA p.Tyr117Serfsa17 | Het | Heterozygous MCP deficiency (low MCP expression on granulocytes) | Novel | Stop gained | No | Pathogenic | 5 |
| 20 | C3 | c.3100T>C; p.Trp1034Arg | Het | Variant located in the TED domain; no identified functional defect | Novel | Probably damaging (1) | No | VUS | |
| 21 | CFI | c.355G>A; p.G119R | Het | Associated with quantitative FI deficiency | 0.05 (rs141853578) | Possibly damaging | Yes | Pathogenic | |
| 22 | CFI | c.1019 T>C; p.Ile340Thr | Het | Variant leading FI quantitative deficiency | 0.004120 | Probably damaging (1) | Yes | Pathogenic | |
| 23 | Anti-FH Ab | High titer at diagnosis (20,000 AU) with homozygous CFHR1/CFHR3 deletion; negative screening at the time of eculizumab discontinuation | Yes |
Variants with documented loss or gain of function of the coded protein are classified as pathogenic variant (previously termed pathogenic mutation). Variants that are predicted to affect the function of the coded protein using bioinformatic tools (i.e., in silico PolyPhen scores or location of the variant in a domain known to be critical to the protein function) but without available functional studies or with limited documented functional effects are classified as likely pathogenic. All others variants are classified as VUS. The frequency of MAF was obtained using the ExAc database Exome Aggregation Consortium (http://exac.broadinstitute.org/about). Pt, patient; Het, heterozygous; Hom, homozygous; MAF, minor allele frequency; PolyPhen-2, Polymorphism Phenotyping v2; aHUS, atypical hemolytic uremic syndrome; CFH, complement factor H; FH, factor H; SCr, serum creatinine; MCP, membrane cofactor protein; VUS, variant of unknown significance; TED, Thioester-containing domain; CFI, complement factor I; FI, factor I.
PolyPhen-2 is a tool that predicts possible effect of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations (http://genetics.bwh.harvard.edu/pph2/).