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| Atypical haemolytic uraemic syndrome v3.9 | CD46 |
Ida Ertmanska changed review comment from: PMID: 40983966 Hu et al., 2025 Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced. PMID: 38317858 Al Riyami et al., 2023 Patient 5 - Omani ancestry - diagnosed with aHUS, heterozygous for CD46 c.175C>T, p.Arg59* (classified Pathogenic / suscept allele) and also het for CFH c.965-6T>C (VUS). PMID: 34169201 Ardissino et al., 2021 Study highlights low penetrance: 2/32 carriers of CD46 mutations (from 16 different families) actually developed aHUS. Two affected carriers harboured CD46 c.98-1G>C and c.286+2T>G splice variants, both classified as LP - second variant also found in 4 healthy family members. Of all 186 individuals with a complement gene abnormality, only 28 developed aHUS - not CD46 specific. PMID: 33224962 Piras et al., 2020 Studied 485 aHUS patients and found CD46 rare variants (RVs) in about 10%. The c.286+2T>G was the most prevalent (13/485) and was associated with <30% penetrance. Reported a large pedigree including a proband het for CD46 c.286+2T>G with severe aHUS and developed end-stage renal failure. The father and paternal uncle with the same variant in homozygosity and six heterozygous relatives are unaffected. Flow cytometry showed about 50% reduction of CD46 expression on blood mononuclear cells from the het proband and over 90% reduction in cells from the proband's unaffected homozygous father and aunt - highlights complexity of aHUS, and that CD46 deficiency may not be enough to induce aHUS. CD46 is associated with AD,AR {Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922 (OMIM accessed 24th Jun 2026). The association between CD46 and semi-dominant atypical hemolytic-uremic syndrome is also classified as Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, June 2024).; to: BIALLELIC CASES: PMID: 40983966 Hu et al., 2025 Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced. Other modifier mutations may affect penetrance here. PMID: 33238263 Bamhraz et al., 2020 Saudi Arabian aHUS cohort. Patient 1 homozygous for CD46: c.736T>A (p.Phe246Ile) variant, as well as het for CFI c.540A>G (p.Glu180Glu) - both labelled VUS. Disease onset at 10yrs, complete recovery after eculizumab treatment. Patient 5 - homozygous for CD46: c.769 C>A (p.Cys 256*) - LP, as well as heterozygous for CFI c.803 C>T (p.Ser268Leu) variant (LB). Disease onset at 2.5yrs, developed into ESRD and required a post-kidney transplant. Patient 7 - homozygous for CD46: c.350-351dup AC (p.Glu11ThfsX17) - LP. Disease onset at 21 months. Patient responded to plasma therapy leading to full recovery. PMID: 29644059 Khandelwal et al., 2018 Cohort of Indian children with aHUS. Sibling pairs 2–3 and 7–8 with familial disease showed a homozygous c.286 + 2T > G splice-site mutation; in both families, the parents were consanguineous. Patient 9 had a homozygous c.104G > A, p.Cys35Tyr; his affected sibling had died before genetic evaluation. 3 unrelated families total. PMID: 14566051 Richards et al., 2003 Family 3 - recessive aHUS, CD46 c.822T>C, p.Ser206Pro. Same mutation caused aHUS in Family 2 in a heterozygous state. Demonstrated that het patients had protein expression reduced by 50%, and it was absent in homozygotes. MONOALLELIC: PMID: 38317858 Al Riyami et al., 2023 Patient 5 - Omani ancestry - diagnosed with aHUS, heterozygous for CD46 c.175C>T, p.Arg59* (classified Pathogenic / suscept allele) and also het for CFH c.965-6T>C (VUS). PMID: 34169201 Ardissino et al., 2021 Study highlights low penetrance: 2/32 carriers of CD46 mutations (from 16 different families) actually developed aHUS. Two affected carriers harboured CD46 c.98-1G>C and c.286+2T>G splice variants, both classified as LP - second variant also found in 4 healthy family members. Of all 186 individuals with a complement gene abnormality, only 28 developed aHUS - not CD46 specific. PMID: 33224962 Piras et al., 2020 Studied 485 aHUS patients and found CD46 rare variants (RVs) in about 10%. The c.286+2T>G was the most prevalent (13/485) and was associated with <30% penetrance. Reported a large pedigree including a proband het for CD46 c.286+2T>G with severe aHUS and developed end-stage renal failure. The father and paternal uncle with the same variant in homozygosity and six het relatives are unaffected. Flow cytometry showed about 50% reduction of CD46 expression on blood mononuclear cells from the het proband and over 90% reduction in cells from the proband's unaffected homozygous father and aunt - highlights complexity of aHUS, and that CD46 deficiency may not be enough to induce aHUS. CD46 is associated with AD,AR {Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922 (OMIM accessed 24th Jun 2026). The association between CD46 and semi-dominant atypical hemolytic-uremic syndrome is also classified as Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, June 2024). |
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| Atypical haemolytic uraemic syndrome v2.17 | CFI | Achchuthan Shanmugasundram Tag Q2_22_MOI was removed from gene: CFI. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.17 | CFI | Achchuthan Shanmugasundram commented on gene: CFI | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.16 | CFI | Achchuthan Shanmugasundram Mode of inheritance for gene CFI was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.15 | CFI | Sarah Leigh Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.15 | CFI | Sarah Leigh commented on gene: CFI: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal in this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.15 | CFI | Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.14 | CFI | Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.13 | CFI | Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.12 | CFI | Sarah Leigh Publications for gene: CFI were set to 16621965; 17597211; 15173250; 23685748 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.11 | CFI | Sarah Leigh edited their review of gene: CFI: Added comment: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal in this panel.; Changed publications to: 17018561, 10352206; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.11 | CFI | Sarah Leigh Tag Q2_22_MOI tag was added to gene: CFI. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v2.11 | CFI | Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3 612923 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v1.7 | CFI | Eleanor Williams reviewed gene: CFI: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v1.6 | CFI |
Eleanor Williams Source NHS GMS was added to CFI. Rating Changed from Green List (high evidence) to Green List (high evidence) |
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| Atypical haemolytic uraemic syndrome | CFI | Sarah Leigh marked CFI as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome | CFI | Sarah Leigh commented on CFI | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||