Clinical whole genome sequencing in pediatric epilepsy: Genetic and phenotypic spectrum of 733 individuals

Abstract

Objective: A large proportion of pediatric epilepsies have an underlying genetic etiology. Limited studies have explored the efficacy of whole genome sequencing (WGS) in a clinical setting. Our academic-clinical center implemented clinical whole exome sequencing (WES) in 2014, then transitioned to WGS from 2015. We report the diagnostic yield, genetic and phenotypic findings, and prognostic factors following WGS/WES in pediatric epilepsy.

Methods: The cohort included 733 families with pediatric epilepsy who received clinical WGS/WES between 2014 and 2022. WGS/WES was performed at the Genomic Medicine Center Karolinska for Rare Diseases and analyzed at the Center for Inherited Metabolic Diseases at Karolinska University Hospital. Phenotypic information was extracted from referrals and medical records. Genetic and phenotypic data were analyzed using descriptive statistics, and univariable and multivariable analyses.

Results: The median age at seizure onset was 9 months. Developmental delay and/or intellectual disability (DD/ID) was observed in 61.3% of the cohort; 38.1% of individuals received an International League Against Epilepsy epilepsy syndrome diagnosis. WGS/WES was performed in 640 (87.3%) and 143 (19.5%) families, respectively, totaling 2029 individuals. A molecular diagnosis was identified in 278 of 733 individuals (37.9%), including 51 of 211 individuals analyzed more than once (24.2% of reanalyzed cases). Independent predictors for receiving a genetic diagnosis included female sex (adjusted odds ratio [aOR] = 1.8, 95% confidence interval [CI] = 1.3-2.4, p < .001), neonatal seizure onset (aOR = 2.5, 95% CI = 1.6-4, p < .001), mortality (aOR = 2.2, 95% CI = 1.3-4.0, p = .0048), and an ID/DD/developmental and epileptic encephalopathy (DEE) diagnosis (aOR = 1.8, 95% CI = 1.2-2.5, p = .0019). The strongest independent predictor of ID/DD/DEE was microcephaly (aOR = 7.8, 95% CI = 2-53, p = .0099). In the solved cohort, gene group did not predict cognitive outcome.

Significance: Clinical WGS is an effective diagnostic tool in pediatric epilepsy. We identified female sex as a novel prognostic factor for receiving a genetic diagnosis and highlight the value of reanalyzing previously unsolved cases to improve diagnostic yield.

Keywords: diagnostic yield; human phenotype ontology; infantile epilepsy; neurodevelopmental disorder; phenotypes; prognosis; real‐world data.

FIGURE 1

Center for Inherited Metabolic Diseases clinical whole genome sequencing (WGS) workflow. The multidisciplinary team is involved in all steps of the analytical process. Dashed arrows/steps 5B–C and 7 represent investigations performed in a subset of individuals where indicated. HPO, human phenotype ontology; IEM, inborn errors of metabolism; MIP, Mutation Identification Pipeline; MLPA, multiplex ligation‐dependent probe amplification. Created in BioRender (Henry [2025], https://BioRender.com/a05d584).

FIGURE 2

Whole cohort phenotypic traits and syndromes. (A) Human Phenotype Ontology (HPO) traits and sex, malformation of cortical development (MCD), any brain malformation, mortality, and epilepsy syndrome diagnosis. (B) Epilepsy syndromes. CAE, childhood absence epilepsy; DD, developmental delay; DEE, developmental and epileptic encephalopathy; EEM, epilepsy with eyelid myoclonia; EE‐SWAS, epileptic encephalopathy with spike‐and‐wave activation in sleep; EIDEE, early infantile DEE; EIMFS, epilepsy of infancy with migrating focal seizures; EMA, epilepsy with myoclonic absences; EMAtS, epilepsy with myoclonic atonic seizures; GEFS+, genetic epilepsy with febrile seizures plus; GGE, generalized epilepsy epilepsy; ID, intellectual disability; IESS, infantile epileptic spasms syndrome; JME, juvenile myoclonic epilepsy; LGS, Lennox–Gastaut syndrome; LKS, Landau–Kleffner syndrome; MEI, myoclonic epilepsy of infancy; MRI, magnetic resonance imaging; PME, progressive myoclonus epilepsy; SeLEAS, self‐limited epilepsy with autonomic seizures; SeLECTS, self‐limited epilepsy with centrotemporal spikes; SeLIE, self‐limited infantile epilepsy; SeLNE, self‐limited neonatal epilepsy; SHE, sleep‐related hypermotor epilepsy.

FIGURE 3

Genetic etiologies in solved individuals. (A) Present in ≥3 individuals across gene groups. (B) Variant types. (C) Mode of inheritance. AD, autosomal dominant; AR, autosomal recessive; comp het, compound heterozygous; homoz, homozygous; mat, maternally inherited; UPD, uniparental disomy; XD, X‐linked dominant; XR, X‐linked recessive. (D) Gene groups. Cell growth: cell growth, division, and proliferation related. Cell structure/homeostasis: cell structural integrity/homeostasis. DNA related: transcription, DNA repair, and chromatin remodeling. Other: other/multiple function proteins. CNV, copy number variant; NT, neurotransmitter; SV, structural variant.

FIGURE 4

Human Phenotype Ontology (HPO) traits and specific developmental and epileptic encephalopathy (DEE) diagnosis, sex, and mortality. (A) Across the 10 highest yield solved genes (n = 106 etiologies). (B) Across gene groups in solved individuals. Darker red indicates higher proportion of specified trait. Cell growth: cell growth, division, and proliferation related. DNA related: transcription, DNA repair, and chromatin remodeling. Other: other/multiple function proteins. DD, developmental delay; ID, intellectual disability; MRI, magnetic resonance imaging; NT, neurotransmitter.