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The patient is right-handed, in early 50s and carries the diagnoses of generalised tonic-clonic seizures, spastic quadriparesis and severe learning disability. Generalised tonic-clonic seizures, the only reported seizure type, occur every few weeks. Current antiseizure drugs include valproate, clonazepam, levetiracetam and lacosamide. Both the patient’s condition and treatment have changed little over the past 11 years for which electronic records are available in the clinic. At best, the patient mobilises with aids and communicates through simple gestures with very limited understanding. The patient attends the clinic with elderly mother and two carers.
Would you try to review the syndromic diagnosis or try to establish a cause?
Guidelines advocate classifying a person’s seizure and epilepsy types, the epilepsy syndrome as well as the underlying cause.1 Reviewing the diagnosis is particularly important when seizures are treatment-resistant.2
From this perspective, the patient’s history of intellectual disability may be particularly important. Although diagnostic yield is higher in children, even among adults with intellectual disability and epilepsy of unknown cause, broad genetic testing may lead to diagnosis in over a quarter of those first tested.3
The patient’s DNA had been previously collected, with appropriate assent, as part of a long-running epilepsy genetics research programme at our centre. The ‘epilepsy plus’ disease category, defined as epilepsy with concomitant intellectual disability, autism spectrum disorder, structural abnormality or unexplained cognitive decline, became available through Genomics England (GEL) in the 100 000 Genomes Project.4 In 2017, the patient’s sample and current diagnoses were entered for analysis.
To anticipate identification of possible clinically relevant findings, we performed screening for stop gain variants in the SCN1A gene region (chr2:165 989 160-166 128 013). This process within the GEL research environment identified the variant c.3796 G>T:p.Glu1266Ter (NM_001165963) in our patient.
How would you approach this finding?
Variants in SCN1A, encoding the alpha subunit of type 1 voltage-gated sodium channel, are associated with a wide range of epilepsies, which may be inherited or arise de …
Collaborators Genomics England Research Consortium contributors: J C Ambrose, P Arumugam, E L Baple, M Bleda, F Boardman-Pretty, J M Boissiere, C R Boustred, H Brittain, M J Caulfield, G C Chan, C E H Craig, L C Daugherty, A de Burca, A Devereau, G Elgar, R E Foulger, T Fowler, P Furió-Tarí, J M Hackett, D Halai, A Hamblin, S Henderson, J E Holman, T J P Hubbard, K Ibáñez, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, L Lahnstein, K Lawson, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, J Mason, E M McDonagh, L Moutsianas, M Mueller, N Murugaesu, A C Need, C A Odhams, C Patch, D Perez-Gil, D Polychronopoulos, J Pullinger, T Rahim, A Rendon, P Riesgo-Ferreiro, T Rogers, M Ryten, K Savage, K Sawant, R H Scott, A Siddiq, A Sieghart, D Smedley, K R Smith, A Sosinsky, W Spooner, H E Stevens, A Stuckey, R Sultana, E R A Thomas, S R Thompson, C Tregidgo, A Tucci, E Walsh, S A Watters, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki.
Contributors KS: drafting of the report; HMC: genetic analysis; Genomics England Research Consortium: generation of genomic data; SB, FR-G and SMS: critical review of the report.
Funding KS is supported by a Wellcome Trust Strategic Award (WT104033AIA). HMC, SB and SMS are supported by the Epilepsy Society. SB is supported by the Muir Maxwell Trust. Part of this work was undertaken at University College London Hospitals, which received a proportion of funding from the NIHR Biomedical Research Centres funding scheme. The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.
Competing interests SMS reports representing the Association of British Neurologists and The Royal College of Physicians (London) at the MHRA Valproate Stakeholders Network, is a member of the scientific advisory board of Dravet Syndrome UK, patron of AHC UK, and has received honoraria or grant funding from UCB, Eisai, Vitaflo and Nutricia. SB has received honoraria from UCB. KS and HMC declare no potential competing interests. FR-G is a committee member of the MHRA Neurology, Pain and Psychiatry Expert Advisory Group and MHRA Sodium Valproate Expert Working Group, and council member of ILAE British branch and has received honoraria from LivaNova.
Patient consent for publication Not required.
Ethics approval The study was approved by the National Research Ethics Service Committee London—Camden and Islington (11/LO/2016).
Provenance and peer review Not commissioned. Externally peer reviewed by Rhys Thomas, Newcastle-upon-Tyne, UK, and Mark Manford, Cambridge, UK.
Data availability statement Data are available to bona fide researchers upon reasonable request and subject to data protection, ethics approval and Genome England requirements.