Presentation: Neonate with unexplained end-stage renal disease

A one-day-old baby on the neonatal unit develops bilious vomiting and abdominal distension in the absence of passing meconium. Bilateral hydronephrosis and an enlarged bladder were identified antenatally. Blood tests show rising urea and creatinine. A contrast study shows impaired peristalsis and microcolon, and an abdominal ultrasound reveals a large, dilated non-obstructed urinary bladder.

Consider genomic testing in the following instances:

• Where no cause has been identified by clinical assessment, biochemistry, imaging or renal biopsy.
• Unexplained end-stage renal disease associated with:
  • atypical growth patterns (overgrowth, asymmetric growth);
  • extra-renal features (for example ocular, hearing loss, neurological, gastrointestinal);
  • a family history of a renal condition or syndrome;
  • dysmorphic facial features or congenital malformations (where targeted testing is not possible); and/or
  • a syndrome, or atypical growth, with intellectual disability or developmental delay.
• Semi-rapid testing can be requested in acutely unwell children or adults where monogenic young onset end-stage renal disease is considered highly likely to be the primary cause of the phenotype. Cases should meet the standard eligibility criteria for test R257 in the National Genomic Test Directory (see more information below). The clinical team should establish that:
  • testing will or could provide an immediate change to treatment or clinical management of the patient, for example by informing decisions about renal transplant, therapeutic intervention or prenatal testing for an ongoing at risk pregnancy; and
  • the patient is either not eligible for the R14 pathway for acutely unwell children or rapid R257 testing is considered to be the more appropriate test.

• 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 panels best suits the needs of your patient/family. For end stage renal diseases, there are a number of available panels including:
  • R257 Unexplained young onset end-stage renal disease: This indication should be considered for patients under the age of 36 presenting with unexplained end-stage renal disease where no cause has been identified by clinical assessment, biochemistry, imaging or biopsy.  This test is carried out using whole genome sequencing (WGS).
  • If there are additional features that suggest a particular diagnosis, consider the following tests:
    • R199 Congenital anomalies of the kidney and urinary tract – familial: This indication should be used if there are clinically significant non-syndromic congenital anomalies of the kidney and urinary tract (CAKUT) and the patient has a first-degree relative with CAKUT or unexplained end-stage renal disease. This test uses microarray. See ‘Child with an ectopic kidney’.
    • R27 Paediatric disorders and R89 Ultra-rare and atypical monogenic disorders: These indications should be considered for individuals with complex or syndromic presentations. R27 includes microarray and a WGS ‘super-panel’. R89 includes microarray and WGS panels selected by the requesting clinician. Both require authorisation from clinical genetics.
    • R240 Diagnostic testing for known mutation(s): This indication is suitable for those who are clinically affected with renal disease and have a family member with 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 presymtomatic) test for those who are unaffected but have a relative with a known pathogenic or likely pathogenic variant. This test requires authorisation from clinical genetics.
• For WGS-based tests, including R257, 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.
• For tests that do not include WGS), including R199, 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. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• These tests are DNA-based, so an EDTA sample (purple-topped tube) is required.

For clinicians

• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory
• US Genetic and Rare Diseases Information Center: Megacystis-microcolon-intestinal hypoperistalsis syndrome

References:

• Eijgelsheim M, De Haan A, Vogt L and others. ‘Diagnostic Yield of Next-Generation Sequencing in Patients with Chronic Kidney Disease of Unknown Etiology’. Frontiers in Genetics 2019: volume 10. DOI: 10.3389/fgene.2019.01264
• Antignac C, Bergmann C, Knoers N and others. ‘Genetic testing in the diagnosis of chronic kidney disease: recommendations for clinical practice’. Nephrology Dialysis Transplantation 2022: volume 37, issue 2, pages 239–254. DOI: 10.1093/ndt/gfab218

For patients

• MMIHS (information and support for people affected by megacystis microcolon intestinal hypoperistalsis syndrome)