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 disorder), 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 abnormality (such as dysmorphism or congenital malformation) and/or unexplained cognitive or memory decline.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• For information on 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:
  • R59 Early onset or syndromic epilepsy: This should be considered when seizures are the main presenting feature. Testing includes microarray and whole genome sequencing (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 disorder such as polymicrogyria) or vascular malformations. It is helpful to distinguish these cases as the sequencing depth is adjusted to enable detection of somatic 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 criteria for rapid WGS (these criteria are: the patient is acutely unwell, there is a likely monogenic disorder, and a molecular diagnosis would be likely to alter management – which may be the case with refractory epilepsy or status epilepticus).
  • R27 Paediatric disorders: Should be considered if the seizures are part of a wider presentation which may include learning difficulties, dysmorphism and/or congenital malformations.
• 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.
• For tests that are undertaken using WGS, including R59 and R27, you will need to:
  • complete an NHS GMS test order form with details of the affected child (proband) and parents, 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 record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion 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).
• For tests that do not include WGS, including R110:
  • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
  • parental samples may be needed for interpretation of the child’s results. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• The majority of 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).
• 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.
• 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:

• 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