Membranoproliferative glomerulonephritis including C3 glomerulopathy

Gene: CFHR5

The mode of inheritance of this gene has been updated to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.

Created: 30 Jan 2023, 4:42 p.m. | Last Modified: 30 Jan 2023, 4:42 p.m.

Panel Version: 2.30

Copy number variants leading to internal duplications or hybrid genes that make elongated CFHR5 proteins cause C3 glomerulopathy via a gain-of-function mechanism (PMID: 32928961; 28729035; 27490940; 33753502). If kidney biopsy is not performed (eg if patient presents with advanced kidney damage) this can present with unexplained end stage kidney disease, typically in males between age 35 and 65. The disease is milder in women (PMID: 20800271; 21566112; 30844074) so AD inheritance may not be apparent. The disease is endemic in Cypriots (PMID: 20800271; 30197990) but is also reported in individual families without Cypriot ancestry (PMID: 24067434; 27490940).

Loss of function or missense variants of this gene are not established causes of kidney disease and have not been described in inherited or familial C3 glomerulopathy.

Created: 7 Apr 2022, 1:12 p.m. | Last Modified: 7 Apr 2022, 1:12 p.m.

Panel Version: 2.22

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Haematuria; C3 glomerulopathy; Chronic Kidney Disease; Proteinuria; End stage renal disease

Publications

• PMID: 20800271
• 21566112
• 30844074
• 28729035
• 32928961
• 24067434
• 27490940
• 33753502
• 30197990
• 24067434

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Variants in this GENE are reported as part of current diagnostic practice

Comment on mode of inheritance: Daniel Gale confirms that the mode of inheritance should be monoallelic only.

Created: 12 Apr 2022, 4:31 p.m. | Last Modified: 12 Apr 2022, 4:31 p.m.

Panel Version: 2.26

Comment on mode of pathogenicity: Updating as per reviewer suggestion

Created: 12 Apr 2022, 4:26 p.m. | Last Modified: 12 Apr 2022, 4:26 p.m.

Panel Version: 2.23

Comment on mode of inheritance: Leaving the mode of inheritance as Both mono and biallelic just now, but only monoallelic cases confirmed so recommending a change to this mode of inheritance.

Created: 4 Apr 2022, 3:24 p.m. | Last Modified: 4 Apr 2022, 3:24 p.m.

Panel Version: 2.22

Associated with Nephropathy due to CFHR5 deficiency #614809 in OMIM (AD) but may be gain-of-function variants that cause pathogenicity.

Looking at the inheritance pattern in the reported cases to check whether the mode of inheritance is correct as Both mono- and bi-allelic. Most reports find that the variants are heterozygous. Only Garam et al 2021 state that more than one variant is found per patient in 2 cases but it is not clear whether these are in one copy or both copies of the gene.

PMID: 20800271 - Gale et al 2010 - report 26 individuals of Cypriot origin and renal disease (C3 glomerulonephritis in the first 2 kindreds) with a heterozygous duplication of exons 2 and 3 of CFHR5 in affected individuals from 11 ostensibly unrelated kindreds.

PMID: 22503529 - Vernon et al 2012 - report a child who developed persistent kidney disease and hypocomplementemia after a streptococcal throat infection. A heterozygous 1 bp insertion was identified in CFHR5, resulting in a premature stop codon. Serum CFHR5 levels were reduced. The mother and sister of the index patient were also heterozygous for the insertion but showed no evidence of kidney disease. The authors suggest that the variant is a risk factor for the development of chronic kidney disease after streptococcal infection.

PMID: 23402027 - Deltas et al 2013 - report a heterozygous duplication of exons 2-3 of the CFHR5 gene in 136 patients from Cyprus. Approx half of patients > 50 years old have progressed to chronic kidney disease and 14% of all patients progressed to ESKD. (Abstract only read)

PMID: 24334459 - Chen et al 2014 - report 2 siblings with C3 glomerulopathy with dense deposit disease (C3G-DDD) in which a deletion of exon 4 of CFHR2 which results in expression of a hybrid CFHR2-CFHR5 plasma protein. The siblings reached ESRD at 20 and 23 years of age. The father also carried the deletion, but was considered healthy, although he showed a low degree of proteinuria and hematuria. The recombinant hybrid protein stabilized the C3 convertase and reduced factor H–mediated convertase decay.

PMID: 24067434 - Medjeral-Thomas et al 2014 - report a family from the UK with no Cypriot ancestry and familial C3 glomerulopathy. In 8 affected family members analysed showed a heterozygous duplication of CFHR5 exons 2 and 3 with a breakpoint different to that seen in Cypriot cases. 3 unaffected individuals did not have the duplication.

PMID: 34566977 - Garam et al 2021 - examined 120 patients with a histologically proven diagnosis of IC-MPGN/C3G. 8 exonic CFHR5 variations (2 frameshift mutations and 6 missense variations) were found in 14 patients. Serum FHR-5 levels were lower in patients compared to controls. However, allele frequencies of some these variants were relatively high (ranging from 0.0002 to 0.0245 in gnomad). 2 patients had more than one variant but it is not clear from the publication whether these were in cis or trans.

Created: 4 Apr 2022, 3:22 p.m. | Last Modified: 4 Apr 2022, 3:22 p.m.

Panel Version: 2.21

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Nephropathy due to CFHR5 deficiency, OMIM:614809

Publications

• 20800271
• 22503529
• 23402027
• 24334459
• 24067434
• 34566977

PMID 22503529 reports a heterozygous 1bp insertion variant (rs565457964) in a child with Nephropathy due to CFHR5 deficiency OMIM:614809 and persistent renal disease following a streptococcal infection. The variant was also seen in her unaffected mother and sister, which suggested that this variant is not sufficient to cause disease, but likely acts as a susceptibility factor for the development of glomerulonephritis.

Created: 7 Apr 2021, 4:29 p.m. | Last Modified: 7 Apr 2021, 4:33 p.m.

Panel Version: 2.20

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

Created: 15 Dec 2017, 3:36 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

• 20800271
• 24067434
• 23728178

Green List (high evidence)

Comment on list classification: Changed to Green but added tag currently-ngs-unreportable

Created: 5 Jun 2017, 3:56 p.m.

Pertinent gene but cannot be reported on : Variants known to be associated to MPGN but cannot be detected due to type of variant consequence which cannot be detected by NGS pipeline. Mutations cause gain of function effects. The pathogenic mutations in CFHR5, CFHR1 and CFHR2 that are known to cause PMG are all gene duplication/fusion/rearrangement events which all lead to the production of elongated proteins, see Gale, 20800271; Tortajada 23728178; Chen, 24334459. Single nucleotide variants (and even frameshifts/premature stop codons) in these particular genes are not (yet) established as pertinent findings since they would be novel compared with what is already known about the genetics of PMG.

Created: 5 Jun 2017, 2:42 p.m.