Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

Joseph D. Symonds, Sameer M. Zuberi (Lead / Corresponding author), Kirsty Stewart, Ailsa McLellan, Mary O'Regan, Stewart MacLeod, Alice Jollands, Shelagh Joss, Martin Kirkpatrick, Andreas Brunklaus, Daniela T. Pilz, Jay Shetty, Liam Dorris, Ishaq Abu-Arafeh, Jamie Andrew, Philip Brink, Mary Callaghan, Jamie Cruden, Louise A. Diver, Christine FindlaySarah Gardiner, Rosemary Grattan, Bethan Lang, Jane MacDonnell, Jean McKnight, Calum A. Morrison, Lesley Nairn, Meghan M. Slean, Elma Stephen, Alan Webb, Angela Vincent, Margaret Wilson

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    Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

    Original languageEnglish
    Pages (from-to)2303-2318
    Number of pages16
    Issue number8
    Early online date13 Jul 2019
    Publication statusPublished - Aug 2019


    • epilepsy
    • genetics
    • epidemiology
    • incidence
    • precision

    ASJC Scopus subject areas

    • Clinical Neurology


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