Presentation: Child with haematuria (blood in the urine)

A child is brought to the outpatient clinic with a history of microscopic (non-visible) haematuria that has been present for the last six months. Haematuria has been identified in the context of a febrile illness and the presence of red blood cells has been confirmed through urine microscopy on several occasions. The urinalysis is otherwise unremarkable and the child is systemically well with blood tests showing normal kidney function.

One of the following must apply:

• There is a first-degree relative who also has haematuria or unexplained chronic kidney disease (CKD).
• Histology supports a diagnosis of Alport syndrome or thin basement membrane nephropathy (TBMN).

There are other clinical features of Alport syndrome (for example, high tone sensorineural hearing loss or characteristic ophthalmic 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.
• Consider which test is most suitable:
  • R194 Haematuria: This indication is likely to be the most appropriate in this scenario. This is a small panel test that incorporates testing for exon-level copy number variants (CNVs) through multiplex ligation-dependent probe amplification (MLPA) or equivalent techniques.
  • If your patient presents with haematuria in the context of a possible syndromic diagnosis, then R27 Paediatric disorders or R89 Ultra-rare and atypical monogenic disorders may be more appropriate tests. R27 and R89 are whole genome sequencing (WGS) tests. (Note that R27 is a large panel that currently requires authorisation from clinical genetics.)
  • If your patient has Cypriot ancestry, R196 CFHR5 nephropathy should be requested initially.
  • R240 Diagnostic testing for known mutation(s): This indication can be used for a patient who is clinically affected with haematuria if a member of their family already has a known pathogenic or likely pathogenic gene 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 for 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, R196, R240, and R242:
  • Use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
  • When testing in children, parental samples may be needed for interpretation of the proband’s result, for example to determine whether a variant is de novo or inherited. These samples may be requested by the testing laboratory or you may wish to contact clinical genetics.
• For WGS-based tests, including R27 and R89, you will need to:
  • Complete an NHS GMS test order form with details of the affected child (proband) and their parents. 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.
  • Submit parental samples alongside the child’s sample where possible to aid interpretation, especially for the larger WGS panels. Where this is not possible, for example if the child is in care and there is no access to parents, or if one parent is unavailable for testing, the child’s sample may still be submitted.
• These tests are DNA-based, so an EDTA sample (purple-topped tube) is required.

• European Renal Association: Precision medicine and hierarchy of diagnostics and treatment in haematuria/proteinuria e-seminar
• GeneReviews: Alport Syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• KDIGO: Clinical Practice Guideline for the Management of Glomerular Diseases
• NHS England: National Genomic Test Directory
• UK Kidney Association: Alport Syndrome
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Savige J, Storey H, Watson E and others. ‘Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria’. European Journal of Human Genetics 2021: volume 29, pages 1,186–1,197. DOI: 10.1038/s41431-021-00858-1
• Kashtan CE, Gross O. ‘Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020’. Pediatric Nephrology 2020: volume 36, issue 3, pages 711–719. DOI: 10.1007/s00467-020-04819-6

Resources for patients

• infoKID (information for parents and carers of children with kidney conditions)
• Kidney Research UK: Alport syndrome
• UK Kidney Association: Alport Syndrome