Presentation: Adult with microscopic haematuria

A 22-year-old male attends the GP due to headaches. A clinical assessment reveals high blood pressure. Subsequent investigations show preserved kidney function with microscopic haematuria and proteinuria. His mother has been told she has microscopic haematuria and his maternal uncle uses hearing aids and has received a kidney transplant. A subsequent kidney biopsy reveals features consistent with Alport syndrome.

• Genomic testing should be considered if someone has persistent haematuria as well as:
  • a first-degree relative with haematuria or unexplained chronic kidney disease (CKD);
  • histological evidence suggestive of Alport syndrome or thin basement membrane disease; or
  • clinical features of Alport syndrome, such as sensorineural hearing loss or ophthalmological features, for example anterior lenticonus or perimacular flecks.
• Also consider facilitating testing for first-degree relatives of affected individuals, especially if potential kidney transplant donors.

• 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.
  • 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 tests best suits the needs of your patient/family:
  • R194 Haematuria: This indication is for a small gene panel test and multiplex ligation-dependent probe amplification (MLPA).
  • R195 Proteinuric renal disease: All gene variants linked with Alport syndrome are included in this panel test. Proteinuria with haematuria is a common presentation of Alport syndrome. This test includes whole exome sequencing (WES) or a medium-sized panel MLPA.
  • R257 Unexplained young onset end-stage renal disease: This indication should be used for patients up to the age of 36 presenting with unexplained end-stage renal disease where no cause has been identified by clinical assessment, biochemistry, imaging or biopsy.  Whole genome sequencing (WGS) is used to analyse a large panel of genes associated with end-stage renal disease.
  • R27 Paediatric disorders: This test investigates chromosomal and monogenic causes in children with a suspected congenital malformation or overgrowth syndrome and developmental delay. It includes microarray and a WGS ‘super-panel’. Authorisation from clinical genetics is required.
  • R89 Ultra-rare and atypical monogenic disorders: This indication should be considered for individuals with an atypical presentation of a complex disorder or malformation, where broad analysis of multiple gene panels that potentially cross different clinical indications is the optimal approach. This test includes microarray and WGS, with panels selected by the requesting clinician. Authorisation from clinical genetics is required.
  • R196 CFHR5 nephropathy: A single gene test for variants in the CFHR5 gene that are associated with nephropathy. This test should be used as a first-line test for any patient presenting with haematuria if they have Cypriot ancestry. (The CFHR5 gene is also included in R197 Membranoproliferative glomerulonephritis including C3 glomerulopathy.)
  • 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 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 and is suitable for unaffected individuals who have a relative with a known pathogenic or likely pathogenic variant. It must be requested by clinical genetics
• For WGS-based tests, including R27, R89 and R257, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband). 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); and
  • complete an NHS GMS record of discussion form for each person being tested. (This is typically one form for an affected individual, but 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.
• For tests that do not include WGS, including R194, R195, R196. R240 and R242:
  •  you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
• 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: 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 – Clinician Information

References:

• Lipska-Zietkiewicz BS, Savige J, Watson E and others. ‘Guidelines for Genetic Testing and Management of Alport Syndrome’. Clinical Journal of the American Society of Nephrology 2022: volume 17, issue 1, pages 143–154. DOI: 10.2215/CJN.04230321

For patients

• Alport UK (for patients and families living with Alport syndrome)
• Kidney Care UK: Alport syndrome
• UK Kidney Association:  Alport Syndrome – Patient Information