Retrospective observational study to determine diagnostic yield and utility of genetic testing in children with epilepsy attending the Epilepsy Clinic at Children’s Hospital, London, Ontario, Canada.

Children (birth–18 years) with epilepsy, who were seen in a 10-year period (January 1, 2008–March 31, 2018), were selected using defined inclusion criteria and by combining clinic datasets and laboratory records.

In total, 105 children (52.38% male and 47.61% female) with a variety of seizures were included in the analysis. Developmental delay was documented in the majority (83; 79.04%). Overall, a genetic diagnosis was established in 24 (22.85%) children. The diagnostic yield was highest for whole-exome sequencing (WES), at 35.71%. The yield from microarray was 8.33%. Yields of single-gene testing (18.60%) and targeted multigene panel testing (19.23%) were very similar. Several likely pathogenic and pathogenic variants not previously reported were identified and categorized using ACMG criteria. All diagnosed patients underwent a review of anti-seizure medication management and received counseling on natural history of their disease, possible complications, recurrence risks, and possibilities of preimplantation or prenatal genetic diagnosis.

Our study confirms the multiple benefits of detecting a genetic etiology in children with epilepsy. Similar yields in single versus multigene testing underscore the importance of accurate clinical phenotyping. Patients with epilepsy and their caregivers in Ontario would undoubtedly benefit from repatriation of multigene panels and WES to the province.

Epilepsy is a common neurological condition that shows a marked genetic predisposition. The advent of next-generation sequencing (NGS) has transformed clinical genetic testing by allowing the rapid screen for causative variants in multiple genes. There are currently no NGS-based multigene panel diagnostic tests available for epilepsy as a licensed clinical diagnostic test in Ontario, Canada. Eligible patient samples are sent out of country for testing by commercial laboratories, which incurs significant cost to the public healthcare system.

An expert Working Group of medical geneticists, pediatric neurologists/epileptologists, biochemical geneticists, and clinical molecular geneticists from Ontario was formed by the Laboratories and Genetics Branch of the Ontario Ministry of Health and Long-Term Care to develop a programmatic approach to implementing epilepsy panel testing as a provincial service.

The Working Group made several recommendations for testing to support the clinical delivery of care in Ontario. First, an extension of community healthcare outcomes-based program should be incorporated to inform and educate ordering providers when requesting and interpreting a genetic panel test. Second, any gene panel testing must be “evidence-based” and takes into account varied clinical indications to reduce the chance of uncertain and secondary results. Finally, an ongoing evaluative process was recommended to ensure continued test improvement for the future.

This epilepsy panel testing implementation plan will be a model for genetic care directed toward a specific set of conditions in the province and serve as a prototype for genetic testing for other genetically heterogeneous diseases.

Population-based studies are necessary to better understand the risk factors for developing seizure disorders and the impact of these conditions on children. We undertook an assessment of the prevalence of seizure disorders in a population of children on the basis of health care utilization records.

Using Manitoba’s population-based prescription and health care data for 1998/99, the prevalence of children with seizure disorders, on the basis of at least one physician visit or hospitalization for epilepsy or a prescription for an antiepileptic drug, was determined by age, urban/rural region and socioeconomic status. The latter was measured as neighbourhoods stratified by income quintiles according to Census data.

Age-specific prevalence rates for seizure disorders in Manitoba children, determined from health care administrative records, were similar to published data on the prevalence of epilepsy, with one exception. Prevalence rates in adolescents were higher than those reported in the literature. No statistically significant differences in prevalence rates were observed between urban and rural populations. However, a higher prevalence was found among children of all ages living in lower socioeconomic neighbourhoods in urban areas, which presented as a gradient of increased prevalence with decreased levels of income.

Population-based health care administrative data can be used to describe the geographical distribution of seizure disorders. Our data suggest that the burden of seizure disorders is not evenly distributed among children.

Multiple sulfatase deficiency (MSD) is a rare autosomal recessive inborn error of lysosomal metabolism. The clinical phenotypic spectrum encompasses overlapping features of variable severity and is suggestive of individual single sulfatase deficiencies (i.e., metachromatic leukodystrophy, mucopolysaccharidosis, and X-linked ichthyosis).

We describe a 3-year-old male with severe hypotonia, developmental regression and progressive neurodegeneration, coarse facial features, nystagmus (from ocular albinism), and dysmyelinating motor sensory neuropathy. Ethics approval was obtained from the Western University Ontario.

Extensive investigative work-up identified deficiencies of multiple sulfatases: heparan sulfate sulfamidase: 6.5 nmoles/mg/protein/17 hour (reference 25.0-75.0), iduronate-2-sulfate sulfatase: 9 nmol/mg/protein/4 hour (reference 31-110), and arylsulfatase A: 3.8 nmoles/hr/mg protein (reference 22-50). The identification of compound heterozygous pathogenic mutations in the SUMF1 gene c.836 C>T (p.A279V) and c.1045C>T (p.R349W) confirmed the diagnosis of MSD.

The complex clinical manifestations of MSD and the unrelated coexistence of ocular albinism as in our case can delay diagnosis. Genetic counselling should be provided to all affected families.