Presentation: Adult with steroid-resistant nephrotic syndrome

A 25-year-old female is referred to the outpatient clinic with nephrotic range proteinuria. She has a known diagnosis of focal segmental glomerulosclerosis (FSGS) after a kidney biopsy. Physical examination reveals absent nails and kneecaps. The proteinuria has not responded to steroid therapy.

You should consider genomic testing in cases of:

• steroid-resistant nephrotic syndrome presenting at any age;
• proteinuria with a histological picture of focal segmental glomerulosclerosis (FSGS) or diffuse mesangial sclerosis (DMS) on biopsy, with no identifiable cause, where a transplant or immunosuppression is planned; or
• a positive family history or presence of syndromic features.

• Consult the National Genomic Test Directory. From this link 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.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our Knowledge Hub resource ‘Genomic testing in the devolved nations’.
  • To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed-Off Panels Resource.
• Decide which of the indications in the test directory best suits the needs of your patient/family:
  • For patients with proteinuria, use R195 Proteinuric renal disease. This test includes a whole genome sequencing (WGS) panel.
  • Other tests to be considered are:
    • R194 Haematuria: This indication should be used in cases of Alport syndrome presenting with FSGS. This test includes a small gene panel test as well as multiplex ligation-dependent probe amplification (MLPA).
    • R220 Wilms tumour with features suggestive of predisposition: This indication should be selected in cases of a Wilms tumour presentation with unexplained proteinuria or kidney failure. This test includes a small gene panel test and MLPA.
  • R257 Unexplained young onset end-stage renal disease: May be considered after expert review, if initial testing does not identify causal gene variants. This test includes a WGS panel.
  • R240 Diagnostic testing for known mutation(s): This indication can be used for a patient who is clinically affected with steroid-resistant nephrotic syndrome if a member of the family 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 a predictive (also known as presymptomatic) test to be used in an unaffected individual where a pathogenic or likely pathogenic variant has already been identified in a relative. This test can only be requested by clinical genetics.
• For tests that do not include WGS, including R194, R220, R240 and R242:
  •  Use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
• For WGS-based tests, including R195 and R257, you will need to:
  • Complete an NHS GMS test order form with details of the affected individual. Include details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see how to complete a test order form for WGS for support).
  • Complete an NHS GMS record of discussion form for each person being tested. If you are undertaking trio testing of an affected individual and their parents, you will need to complete three forms. See how to complete a record of discussion form for support.
• These tests are DNA-based, so an EDTA sample (purple-topped tube) is required.

For clinicians

• European Renal Association: Precision medicine and hierarchy of diagnostics and treatment in haematuria/proteinuria e-seminar
• GeneReviews: Genetic Steroid-Resistant Nephrotic Syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory
• Orphanet: Genetic steroid-resistant nephrotic syndrome
• UK Kidney Association: The UK eCKD Guide

For patients

• Kidney Research UK: Nephrotic syndrome
• The Nephrotic Syndrome Trust