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Nephrology

Presentation: Young person with idiopathic C3 glomerulopathy

Primary C3 glomerulopathy, sometimes known as membranoproliferative glomerulonephritis, may have a genetic cause, especially when there is family history of the condition or first-degree relatives with unexplained end-stage renal disease.

Example clinical scenario

A 16-year-old male is referred to nephrology with proteinuria, haematuria and hypertension. Investigations show nephrotic-range proteinuria and reduced eGFR with a slightly low serum C3 and negative C3 nephritic factor. His brother had been diagnosed with unexplained end-stage renal disease at age 21. Subsequent kidney biopsy is in keeping with C3 glomerulopathy (C3GN) and there is an absence of dense deposits.

When to consider genomic testing

You should consider genomic testing if your patient has idiopathic membranoproliferative glomerulonephritis (MPGN) or C3GN with onset before the age of 18 and: 

  • has a family history of MPGN/C3GN or unexplained end-stage renal disease;
  • a renal transplant is being considered; or
  • the patient is being considered for complement inhibitory therapies such as eculizumab.

There should also be no evidence of secondary cause, for example your patient could be post-infection or have a paraprotein.

C3GN is caused by variants in complement genes in only a minority of cases. There is a higher prevalence in patients with Cypriot ancestry; for further information about testing in this context see ‘Patient of Cypriot descent presents with reduced renal function and microscopic haematuria’.

A histological diagnosis of MPGN, in which immune complex deposition is prominent, does not exclude a genetic cause, but most MPGN is associated with autoimmune, infectious or proliferative disease and these should be considered and excluded first. Patients with C3 nephritic factor or dense deposits are less likely to have a genetic cause.

What do you need to do?

  • Consult the National Genomic Test Directory. Here you can access the rare and inherited disease eligibility criteria document for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • Consider which of the following tests is best suited to your patient/family:
    • R197 Membranoproliferative glomerulonephritis including C3 glomerulopathy: This test is the first choice for patients who meet the criteria detailed above. It includes multiplex ligation-dependent probe amplification (MLPA) and a panel test comprising of genes in which variants are known to cause MPGN.
    • R240 Diagnostic testing for known mutation(s): This indication can be used when a patient is clinically affected by idiopathic C3GN if a member of the family already has a known pathogenic or likely pathogenic variant. In this situation, the laboratory will only test for the known familial variant.
    • R242 Predictive testing for known familial mutation(s): This indication is for a predictive (also known as presymptomatic) test that should be used for unaffected individuals who have a family member with a known pathogenic or likely pathogenic variant. This test requires authorisation from clinical genetics.
  • The tests listed above do not involve whole genome sequencing (WGS):
  • These tests are DNA-based, so an EDTA sample (purple-topped tube) is required.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 08/07/2024
  • Next review due: 08/07/2025
  • Authors: Dr Lauren Cairns, Dr David Zocche
  • Reviewers: Dr Danielle Bogue , Dr Katherine Bull, Dr Daniel Gale, Professor Richard Sandford

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