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); or
• 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 here you can access the rare and inherited disease eligibility criteria 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 Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Consider which test is most suitable:
  • The most appropriate in this scenario is likely to be:
    • R194 Haematuria: 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:
    • R27 Paediatric disorders: This may be a more appropriate test. It is a whole genome sequencing (WGS) test. R27 is an amalgamation of over 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
  • If your patient has Cypriot ancestry:
    • R196 CFHR5 nephropathy: This should be requested initially.
  • R240 Diagnostic testing for known variant(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 variant(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:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
• For tests that are undertaken using WGS, including R27, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where available, including 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 in completing WGS-specific forms).
• When testing in children, parental samples may be helpful for interpretation of the proband’s result. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

• 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 and 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