Presentation: Child acutely unwell in NICU or PICU

A neonate is delivered at 32 weeks’ gestation due to fetal distress. Antenatal imaging revealed fetal hydrops with ascites, bilateral pleural effusions and a pericardial effusion, the cause of which is unknown. Since birth, the baby has remained critically unwell in NICU and has dysmorphic features including low-set ears, micrognathia, widely spaced nipples and a flat nasal bridge.

Consider genomic testing if:

• a neonate or child is admitted to NICU or PICU with a presentation that is likely to result from a single gene (monogenic) disorder;
• a neonate or child is admitted to NICU or PICU with any of the following (and an alternate diagnosis is unavailable):
  • congenital anomalies (two major or one major together with neurological signs, dysmorphic features, aberrant growth or unusual behaviour);
  • neurological signs (such as refractory seizures, encephalopathy, significant abnormalities of tone or a progressive neuromuscular disorder);
  • suspected metabolic or mitochondrial disease; and/or
  • extreme intrauterine growth restriction or failure to thrive; and/or
• a critically unwell neonate or child is presenting without a clear unifying diagnosis.

• 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.
• Guidance on the most appropriate test to request, and assistance with panel selection may be sought from discussion with your local genetics team.
• Decide which of the panels best suits the needs of your patient or family and discuss the case with your local clinical geneticist. For acutely unwell children in NICU or PICU, the following panels should be considered:
  • R14 Acutely unwell children with a likely monogenic disorder: This should be considered if the patient fulfils the criteria for rapid whole genome sequencing (WGS) provided by the Exeter Genetics Laboratory. The criteria are: the patient is acutely unwell, there is a likely monogenic disorder and molecular diagnosis is likely to imminently alter management;
  • R26 Likely common aneuploidy testing: This should be performed first if aneuploidy (trisomy 13, 18 or 21) is considered to be the most likely diagnosis;
  • R28 Congenital malformation and dysmorphism syndromes – microarray only: This should be considered if a multisystem syndrome with a possible chromosomal diagnosis is suspected. Where possible, the chromosomal condition suspected should be specified on the test request form. R28 may be requested as urgent for neonates/children in NICU/PICU, with results anticipated within two weeks.
    • If the patient is eligible for R14, you do not need to request R28 as copy number variants will be analysed through R14.
  • R27 Paediatric disorders: This is a WGS multi-panel test that may be considered for patients who require broad genomic testing. Both chromosomal and single-gene analyses are completed. Additional panels relevant to the patient phenotype can also be added, provided the analysis is as a trio (both parents and child). In those not eligible for R14 but where a ‘soon’ result would be beneficial, a prioritised analysis may be requested with results expected in 6–8 weeks.
• R14 is a WGS test that looks agnostically across the entire genome. Currently, prior authorisation is required from clinical genetics. There is a specific test order form and RoD form for this test; both are available from the Exeter Genetics Laboratory.
• 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.
• For tests that do not include WGS, including R27:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms; and
  • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• For tests that are undertaken using WGS, including R26 and R28, 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); and
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected individual and their parents, you will need three RoD forms (see How to complete a RoD form for support); and
  • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• 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.

For clinicians

• Exeter Clinical Laboratory International: R14 Rapid Genome Sequencing Service
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• French CE, Delon I, Dolling H and others. ‘Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children’. Intensive Care Medicine 2019: volume 45, issue 5, pages 627–636. DOI: 0.1007/s00134-019-05552-x
• Sparks TN, Lianoglou BR, Adami RR and others. ‘Exome sequencing for prenatal diagnosis in nonimmune hydrops fetalis’. The New England Journal of Medicine 2020: volume 383, issue 18, pages 1,746–1,756. DOI: 10.1056/NEJMoa2023643

For patients

• NHS England: Whole genome sequencing patient information leaflets
• Exeter Clinical Laboratory International: R14 Patient Information Leaflet (PDF, two pages)