Presentation: Adult with epilepsy likely to be genetic in origin

A patient with a diagnosis of autism and moderate intellectual difficulties attends clinic with a family member. Her relative reports that she attended the emergency department as a young child with a few suspected self-remitting seizures and that, after a long period of seizure freedom, she is now experiencing recurrence.

Most patients whose epilepsy has a genetic cause present in childhood. Not every patient who experiences seizures in childhood will have a genetic cause, and not all will have been offered genomic testing. For this reason, genomic testing should be aimed at those patients in whom it is most likely to identify a genetic diagnosis.

Clinical features suggestive of specific genetic epilepsy include:

• onset of seizures under the age of two;
• associated intellectual difficulties, which may or may not pre-date seizures (neurodevelopmental conditions such as an autistic spectrum disorder may co-exist);
• associated neurodegenerative features;
• systemic features suggestive of mitochondrial aetiology such as mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS);
• one or more first-degree relative(s) with seizures or febrile convulsions and/or intellectual difficulties; and
• associated developmental structural anomalies such as polymicrogyria.

Factors unlikely to be associated with genetic epilepsy include:

• adult-onset seizures with neurotypical intellectual performance;
• absence of systemic features; and
• acquired or secondary causes of epilepsy, such as tumours or hippocampal sclerosis.

Urgent testing is available in exceptional circumstances. This should be considered if the patient fulfils the criteria for rapid whole genome sequencing (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.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria document, which contains 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.
• 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 and/or their family. For patients with epilepsy, there are three main panels with overlap in the included genes.
  • R59 Early onset or syndromic epilepsy: This gene panel should be used for all patients with early onset epilepsy, and for those in whom a syndromic or neurodegenerative epilepsy diagnosis is suspected. It is carried out by WGS, though only genes associated with seizures are analysed.
  • R29 Intellectual disability: This panel investigates chromosomal and single-gene causes of developmental delay and intellectual disability. It is a WGS test, though only genes known to cause intellectual disability are analysed.
  • R87 Cerebral malformation: This can be requested for patients with changes in brain development, such as cortical dysplasia or polymicrogyria, identified on brain imaging.
  • R315 POLG-related disorder: This should be used in cases in which there is a high clinical suspicion of POLG-related disease.
  • R14 Acutely unwell children with a likely monogenic disorder: Requests for this indication in adults is expected to be only under exceptional circumstances. Urgent testing may only be requested following discussion with the local Clinical Genetics service and the Exeter Clinical Laboratory. Please see the R14 Knowledge Hub resource for details of testing.
• For patients in whom there is a clinical suspicion of a mitochondrial condition, a different diagnostic pathway with early involvement of specialist services may be required.
• For tests that are undertaken using WGS, such as R59 and R29, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number(s) (see How to complete a test order form for WGS);
  • 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 patient and their parents, you will need three RoD forms (see How to complete a RoD form);
  • submit a consultee form signed by an appropriate relative or advocate if the patient does not have capacity to consent to genomic testing; and
  • submit parental samples alongside the affected individual’s sample (if parental samples are available) to aid interpretation, especially for the larger WGS panels. Where this is not possible, the patient may be submitted as a singleton.
• For tests that do not include WGS, such as R315:
  • you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms; and
  • if parental samples are available and will aid interpretation of the proband’s result, samples can be taken alongside that of the proband, and the DNA stored, or can be requested at a later date if needed.
• The tests outlined above are DNA-based, and an EDTA sample (typically a purple-topped tube) is required.
• Information about patient eligibility and test indications were 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 GMS Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Johannesen KM, Marjanovic D, Nikanorova N and others. ‘Utility of genetic testing for therapeutic decision-making in adults with epilepsy’. Epilepsia 2020: volume 61, issue 6, pages 1,234–1,239. DOI: 10.1111/epi.16533

For patients

• Epilepsy Action