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.
• Features of a specific genetic epilepsy syndrome, such as Dravet syndrome.
• Associated intellectual difficulties, which may or may not pre-date seizures (neurodevelopmental conditions such as an autistic spectrum disorder may co-exist). Note that in the absence of other features, testing is available to those with unexplained moderate/severe/profound intellectual disability. Testing of those with mild intellectual disability or isolated neurodevelopmental disorders should only be considered if there are additional features to indicate an underlying clinical syndrome.
• 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.
• Associated developmental structural anomalies such as polymicrogyria.

In cases where there is a combination of the features listed above, more than one test may be relevant. For example, if a patient has early-onset seizures, moderate intellectual disability, developmental brain malformation and microcephaly, you may request a combination of panels looking for causes of all four clinical features. Clinicians are encouraged to request all relevant panels at the time of referral.

In this group of patients, it is beneficial to include both parents in genomic testing (known as trio testing) IF the test being undertaken involves whole genome sequencing (WGS). Evidence shows that this improves diagnostic rate and variant interpretation. Every effort should be taken to include parental samples (if available) alongside those from the proband when first requesting WGS as they cannot be added at a later date.

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 WGS through the R14 testing pathway. These criteria are that: the patient is acutely unwell; there is a high likelihood of a 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 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.
• Where a specific diagnosis, such as tuberous sclerosis complex, is thought likely – see ‘Clinical suspicion of tuberous sclerosis complex‘ – and targeted testing is available, this should be considered first.
• Decide which of the tests 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. Analysis includes short tandem repeat (STR) testing for the ATN and CSTB genes associated with dentatorubral-pallidoluysian atrophy (DRPLA) and progressive myoclonic epilepsy type 1A (known as Unverricht-Lundborg disease) respectively.
  • R27 Paediatric disorders: The R27 test indication is the preferred choice when there is a high likelihood of a syndrome that affects other body systems, including congenital malformations (for example congenital heart disease) and/or dysmorphic features. This is a WGS panel that includes both the R59 and R29 gene panels. It may be necessary to discuss testing in an adult with your regional clinical genetics team prior to request.
  • R29 Intellectual disability: This WGS-based panel investigates chromosomal and single-gene causes of unexplained moderate/severe/profound developmental delay and intellectual disability. Genes known to cause intellectual disability are included and analysis includes STRs.
  • R87 Cerebral malformation: This WGS-based panel can be requested for patients with changes in brain development, such as cortical dysplasia or polymicrogyria, identified on brain imaging.
  • R88 Severe microcephaly: This WGS-based panel can be requested where the patient meets clinical criteria and is typically associated with intellectual disability.
  • R315 POLG-related disorder: This should be used in cases in which there is a high clinical suspicion of POLG-related disease. See ‘Adult with suspected 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, including R59, R27, R87, R88, R29 and R14, 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 for support);
  • 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 for support); and
  • obtain a consultee form signed by an appropriate relative or advocate if the patient does not have capacity to consent to genomic testing.
• For tests that do not include WGS, including R315:
  • • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
• 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 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