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

Abstract

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.

Diagnostic Yield of Epilepsy Panel Testing in Patients With Seizure Onset Within the First Year of Life

“…In the present study, a genetic etiology for nearly half of the patients (47.3%) with infantile-onset epilepsy was identified. The higher diagnostic yield in this age group was recently demonstrated in a prospective population-based study by Symonds et al (26). They prospectively recruited patients whose seizure onset was before 36 months of age.…”

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

“…At this early stage, genetic testing results are often not yet available and may take weeks or months to conclude. However, there is robust population‐ and cohort‐based evidence showing that the genetic epilepsies commonly presenting at this early age (<3 months) are KCNQ2 , KCNQ3 , CDKL5 , SCN2A, and STXBP1 , but not SCN1A . These young infants will in the majority of cases respond to SCBs without the expectation for seizures to worsen when SCBs are given.…”

“…However, there is robust population-and cohort-based evidence showing that the genetic epilepsies commonly presenting at this early age (<3 months) are KCNQ2, KCNQ3, CDKL5, SCN2A, and STXBP1, but not SCN1A. 54,55 These young infants will in the majority of cases respond to SCBs without the expectation for seizures to worsen when SCBs are given. The theoretical risk of seizure exacerbation due to SCBs is comparatively low, because we show how unlikely SCN1A variants are to present at this young age.…”

Childhood neurodegeneration associated with a specific UBTF variant: a new case report and review of the literature

“…The raw data from Whole Exome Sequencing (WES) were screened using an in-house pipeline as previously described [6] allowing for filtering of synonymous and common variants to which a panel of approximately 1300 genes known to be implicated in developmental delay and seizure disorders was applied. The original analysis failed to yield any variant that might be plausibly linked to an intellectual disability or epilepsy phenotype [7]. The data were reanalyzed six months later using an updated panel that (at that point) contained the gene UBTF, that had just been published in connection with an intellectual disability phenotype by Edvardson et al [1].…”