Membranoproliferative glomerulonephritis including C3 glomerulopathy

Gene: CFI

Green List (high evidence)

PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Of note, 90% of CFI variants identified in patients have been reported in gnomAD (most CFH variants are absent), suggesting that genetic susceptibility induced by CFI variants may be lower than those of CFH variants.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants".

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFI and AD C3 glomerulonephriti has been classified as Moderate in ClinGen (June 2024); association with AD atypical hemolytic-uremic syndrome was ranked as Definitive (June 2023).

Created: 4 Jun 2026, 12:20 p.m. | Last Modified: 4 Jun 2026, 1:19 p.m.

Panel Version: 3.13

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
{Hemolytic uremic syndrome, atypical, susceptibility to, 3}, OMIM:612923; Complement factor I deficiency, OMIM:610984

Publications

• 26895476
• 26283675
• 31919107
• 37615951

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains green.

The following is the comment from GMS reviewers:
The target is included in current screening. Sequence data provides clinically informative information to the NRCTC. An audit of genotype:phenotype correlation is ongoing with in the NRCTC with a completion date in the New Year. We are requesting that this target remains within the panel to enable collation of audit data.

Created: 4 Dec 2024, 10:37 p.m. | Last Modified: 6 Dec 2024, 10:39 a.m.

Panel Version: 3.6

Comment on list classification: Changed rating to Green to reflect NHS signed-off rating, will be examined at next panel review.

Created: 16 Oct 2020, 8:10 a.m. | Last Modified: 16 Oct 2020, 8:10 a.m.

Panel Version: 2.12

Red List (low evidence)

There are no reports I am aware of of mutations in this gene co-segregating with familial MPGN. Therefore this should not be regarded as a diagnostic gene. Rare variants have been reported in patients with MPGN in uncontrolled candidate gene sequencing studies.

Created: 10 Jan 2020, 10:26 a.m. | Last Modified: 10 Jan 2020, 10:26 a.m.

Panel Version: 2.2

Mode of inheritance
Unknown

Red List (low evidence)

Comment on list classification: Changing rating from Green to Amber. Expert review has rated this gene red. No famililal cases reported, and cases that are reported looked at candidate genes only.

Created: 23 Mar 2020, 11:37 a.m. | Last Modified: 23 Mar 2020, 11:37 a.m.

Panel Version: 2.8

Only renal phenotype in OMIM this gene is associated with is {Hemolytic uremic syndrome, atypical, susceptibility to, 3} 612923.

Papers cited by the BRIDGE consortium
PMID: 18371543 - Boyer et al 2008 - Patient 1 with atypical hemolytic and uremic syndrome had combined CFH and CFI heterozygous mutations.

PMID: 22456601 - Servais et al 2012 - for 141 patients from 45 centers with a definite diagnosis of primary MPGN I, DDD, or GNC3 they performed direct sequencing of CFH, CFI, or MCP exons and of a set of 10 SNPs within the CFH and MCP genes. 6 patients had heterozygous variants in CFI, 3 of which are reported in patients with MPGN histology (Table 2).

Following expert review rating this gene Red, and review of the literature this gene should be down graded to Amber or Red.

Created: 29 Jan 2020, 10:25 p.m. | Last Modified: 29 Jan 2020, 10:25 p.m.

Panel Version: 2.2

This gene was part of an initial gene list collated by Valerie Wilson, The National Renal Complement Therapeutics Centre, February 2019 on behalf of Yorkshire and North East GLH for the GMS Renal Specialist Test Group; Gene Symbol submitted: CFI; Suggested initial gene rating: none provided;

Created: 12 Feb 2019, 12:13 p.m.

Comment when marking as ready: Marked as ready after clinical review

Created: 15 Dec 2017, 3:40 p.m.

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN

Publications

• 18371543
• 22456601

Green List (high evidence)

Pertinent gene. The variants known to be associated to MPGN - Genes against which can be detected with current pipeline (Single nucleotide variants/frameshifts/premature stop codon etc)

Created: 5 Jun 2017, 2:43 p.m.