Presentation: Infant with early onset epilepsy or epileptic encephalopathy

An eight-month-old infant presents with a prolonged afebrile seizure. He has had two previous afebrile seizures, and all his seizures have been hemiclonic. The first two involved his right side, and the most recent involved his left side. The seizures have been prolonged, and have required two doses of benzodiazepines prior to terminating. His examination is normal, he is not dysmorphic, he is reaching his milestones and there is no family history of epilepsy. His EEG is normal.

• Genomic testing should be considered if the cause of a patient’s epilepsy is unexplained and there is a clinical suspicion of a single gene cause (monogenic condition), including:
  • onset under two years of age;
  • clinical features suggestive of a specific genetic epilepsy, for example Dravet syndrome or SLC2A1/GLUT1 deficiency; and/or
  • additional clinical features are present, such as intellectual disability, autism spectrum disorder, structural anomaly (such as dysmorphism or congenital malformation) and/or unexplained cognitive or memory decline.
• Rapid agnostic trio whole genome sequencing (WGS) may be appropriate for acutely unwell children with a likely monogenic condition in whom testing is likely to provide an immediate change in clinical management. Examples of relevant conditions include epileptic encephalopathy and neonatal-onset epilepsy.

• 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.
• Decide which of the panels best suit the needs of your patient or family. The choice of panel will be determined by the age of the child, the clinical findings and the diagnoses that are being considered. For suspected monogenic epilepsies there are a number of panels that may be relevant, including:
  • R27 Paediatric disorders: Should be considered where there is unexplained epilepsy with a clinical suspicion of a monogenic cause, including onset under two years, or where clinical features are suggestive of a specific genetic epilepsy, such as Dravet syndrome. R27 is also appropriate for individuals in whom seizures are present alongside wider features, such as learning difficulties, dysmorphism and/or congenital malformations. Testing is by WGS.
  • R110 Segmental overgrowth disorders – Deep sequencing: This should be requested where there are features of segmental overgrowth such as a larger limb or digit, megalencephaly (with or without a neuronal migration condition such as polymicrogyria) or vascular malformations. It is helpful to distinguish these cases, as the sequencing depth is adjusted to enable detection of somatic (acquired) mosaic variants that may be responsible; other panels may not detect these variants.
  • R14 Acutely unwell children with a likely monogenic disorder: This should be considered if the patient fulfils the following criteria for rapid WGS:
    • the patient is acutely unwell;
    • there is a likely monogenic condition; and
    • a molecular diagnosis would be likely to alter management (which may be the case with refractory epilepsy or status epilepticus).
• Note that if the clinical presentation and biochemical testing suggest a metabolic or mitochondrial cause, testing should be conducted under an alternative metabolic or mitochondrial-related indication.
• R14 is a WGS test that looks agnostically across the entire genome. Requesting it currently requires authorisation from clinical genetics. There is a special test order form and RoD form for this test, both of which 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 conditions. 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 R110:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion, or RoD) 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 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);
  • complete an NHS GMS 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);
  • obtain a consultee form signed by an appropriate relative or advocate if an adult patient does not have capacity to consent to genomic testing; and/or
  • submit parental samples alongside the child’s sample 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. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube). For more information, 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

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Guerrini R, Balestrini S, Wirrell EC and others. ‘Monogenic epilepsies: Disease mechanisms, clinical phenotypes, and targeted therapies‘. Neurology 2021: volume 97, issue 17, pages 817–831. DOI: 10.1212/WNL.0000000000012744
• Perry LD, Hogg SL, Bowdin S and others. ‘Fifteen-minute consultation: The efficient investigation of infantile and childhood epileptic encephalopathies in the era of modern genomics’. Archives of Disease in Childhood Education and Practice Edition 2022: volume 107, issue 2, pages 80–87. DOI: 10.1136/archdischild-2020-320606

For patients

• Epilepsy Action: Your child’s epilepsy
• Epilepsy Foundation
• NHS England: Whole genome sequencing patient information leaflets