Medicine (Austin & Northern Health) - Research Publications

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    Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals
    Morison, LD ; Kennis, MGP ; Rots, D ; Bouman, A ; Kummeling, J ; Palmer, E ; Vogel, AP ; Liegeois, F ; Brignell, A ; Srivastava, S ; Frazier, Z ; Milnes, D ; Goel, H ; Amor, DJ ; Scheffer, IE ; Kleefstra, T ; Morgan, AT (BMJ PUBLISHING GROUP, 2024-01-30)
    OBJECTIVES: Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome. METHOD: 103 individuals with Kleefstra syndrome (40 males, median age 9.5 years, range 1-43 years) with pathogenic variants (52 9q34.3 deletions, 50 intragenic variants, 1 balanced translocation) were included. Speech, language and non-verbal communication were assessed. Cognitive, health and neurodevelopmental data were obtained. RESULTS: The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%). Language ability also ranged from average intelligence (10/90, 11%) to severe intellectual disability (53/90, 59%). Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition. Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains. Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression. CONCLUSIONS: The speech, language and cognitive profile of Kleefstra syndrome is broad, ranging from severe impairment to average ability. Genotype and age do not explain the phenotypic variability. Early access to communication aids may improve communication and quality of life.
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    Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40
    Morgan, AT ; Scerri, TS ; Vogel, AP ; Reid, CA ; Quach, M ; Jackson, VE ; McKenzie, C ; Burrows, EL ; Bennett, MF ; Turner, SJ ; Reilly, S ; Horton, SE ; Block, S ; Kefalianos, E ; Frigerio-Domingues, C ; Sainz, E ; Rigbye, KA ; Featherby, TJ ; Richards, KL ; Kueh, A ; Herold, MJ ; Corbett, MA ; Gecz, J ; Helbig, I ; Thompson-Lake, DGY ; Liegeois, FJ ; Morell, RJ ; Hung, A ; Drayna, D ; Scheffer, IE ; Wright, DK ; Bahlo, M ; Hildebrand, MS (OXFORD UNIV PRESS, 2023-12-01)
    Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.
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    Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature.
    LaFlamme, CW ; Rastin, C ; Sengupta, S ; Pennington, HE ; Russ-Hall, SJ ; Schneider, AL ; Bonkowski, ES ; Almanza Fuerte, EP ; Galey, M ; Goffena, J ; Gibson, SB ; Allan, TJ ; Nyaga, DM ; Lieffering, N ; Hebbar, M ; Walker, EV ; Darnell, D ; Olsen, SR ; Kolekar, P ; Djekidel, N ; Rosikiewicz, W ; McConkey, H ; Kerkhof, J ; Levy, MA ; Relator, R ; Lev, D ; Lerman-Sagie, T ; Park, KL ; Alders, M ; Cappuccio, G ; Chatron, N ; Demain, L ; Genevieve, D ; Lesca, G ; Roscioli, T ; Sanlaville, D ; Tedder, ML ; Hubshman, MW ; Ketkar, S ; Dai, H ; Worley, KC ; Rosenfeld, JA ; Chao, H-T ; Undiagnosed Diseases Network, ; Neale, G ; Carvill, GL ; University of Washington Center for Rare Disease Research, ; Wang, Z ; Berkovic, SF ; Sadleir, LG ; Miller, DE ; Scheffer, IE ; Sadikovic, B ; Mefford, HC (Cold Spring Harbor Laboratory, 2023-10-12)
    Sequence-based genetic testing currently identifies causative genetic variants in ∼50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. Rare epigenetic variations ("epivariants") can drive disease by modulating gene expression at single loci, whereas genome-wide DNA methylation changes can result in distinct "episignature" biomarkers for monogenic disorders in a growing number of rare diseases. Here, we interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 516 individuals with genetically unsolved DEEs who had previously undergone extensive genetic testing. We identified rare differentially methylated regions (DMRs) and explanatory episignatures to discover causative and candidate genetic etiologies in 10 individuals. We then used long-read sequencing to identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and two copy number variants. We also identify pathogenic sequence variants associated with episignatures; some had been missed by previous exome sequencing. Although most DEE genes lack known episignatures, the increase in diagnostic yield for DNA methylation analysis in DEEs is comparable to the added yield of genome sequencing. Finally, we refine an episignature for CHD2 using an 850K methylation array which was further refined at higher CpG resolution using bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate genetic causes as ∼2% (10/516) for unsolved DEE cases.
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    Perisylvian and Hippocampal Anomalies in Individuals With Pathogenic GRIN2A Variants
    Thompson-Lake, DGY ; Liegeois, FJ ; Braden, RO ; Jackson, GD ; Turner, SJ ; Morison, L ; Hildebrand, M ; Scheffer, IE ; Morgan, AT (Wolters Kluwer, 2024-04)
    Background and Objectives: Pathogenic variants in GRIN2A are associated with a spectrum of epilepsy-aphasia syndromes (EASs). Seizures as well as speech and language disorders occur frequently but vary widely in severity, both between individuals and across the life span. The link between this phenotypic spectrum and brain characteristics is unknown. Specifically, altered brain networks at the root of speech and language deficits remain to be identified. Patients with pathogenic variants in GRIN2A offer an opportunity to interrogate the impact of glutamate receptor dysfunction on brain development. Methods: We characterized brain anomalies in individuals with pathogenic GRIN2A variants and EASs, hypothesizing alterations in perisylvian speech-language regions and the striatum. We compared structural MRI data from 10 individuals (3 children and 7 adults, 3 female) with pathogenic GRIN2A variants with data from age-matched controls (N = 51 and N = 203 in a secondary analysis). We examined cortical thickness and volume in 4 a priori hypothesized speech and language regions (inferior frontal, precentral, supramarginal, and superior temporal) and across the whole brain. Subcortical structures (hippocampus, basal ganglia, thalamus) and the corpus callosum were also compared. Results: Individuals with pathogenic GRIN2A variants showed increased thickness and volume in the posterior part of Broca's area (inferior frontal gyrus, pars opercularis). For thickness, the effects were bilateral but more pronounced in the left (large effect size, η2 = 0.37) than the right (η2 = 0.12) hemisphere. Both volume and thickness were also higher in the bilateral superior temporal region while the supramarginal region showed increased thickness only. Whole-brain analyses confirmed left-sided thickness increases in Broca's area, with additional increases in the occipital and superior frontal cortices bilaterally. Hippocampal volume was reduced in the left hemisphere. There were no age-dependent effects or corpus callosum group differences. Discussion: Anomalies in perisylvian regions, with largest differences in Broca's area, suggest an altered development of classical speech-language networks in GRIN2A-related EAS. Left hippocampal reduction suggests a role for this structure in early speech and language development and is consistent with GRIN2A gene expression in that region. Overall, elucidating the neural correlates of EAS provides insights into the impact of GRIN2A dysfunction, opening avenues for targeted intervention in developmental syndromes with compromised speech-language development.
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    Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study
    Perry, MS ; Scheffer, IE ; Sullivan, J ; Brunklaus, A ; Boronat, S ; Wheless, JW ; Laux, L ; Patel, AD ; Roberts, CM ; Dlugos, D ; Holder, D ; Knupp, KG ; Lallas, M ; Phillips, S ; Segal, E ; Smeyers, P ; Lal, D ; Wirrell, E ; Zuberi, S ; Bruenger, T ; Wojnaroski, M ; Maru, B ; O'Donnell, P ; Morton, M ; James, E ; Vila, MC ; Huang, N ; Gofshteyn, JS ; Rico, S (WILEY, 2024-02)
    OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.
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    Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5.
    Happ, HC ; Sadleir, LG ; Zemel, M ; de Valles-Ibáñez, G ; Hildebrand, MS ; McConkie-Rosell, A ; McDonald, M ; May, H ; Sands, T ; Aggarwal, V ; Elder, C ; Feyma, T ; Bayat, A ; Møller, RS ; Fenger, CD ; Klint Nielsen, JE ; Datta, AN ; Gorman, KM ; King, MD ; Linhares, ND ; Burton, BK ; Paras, A ; Ellard, S ; Rankin, J ; Shukla, A ; Majethia, P ; Olson, RJ ; Muthusamy, K ; Schimmenti, LA ; Starnes, K ; Sedláčková, L ; Štěrbová, K ; Vlčková, M ; Laššuthová, P ; Jahodová, A ; Porter, BE ; Couque, N ; Colin, E ; Prouteau, C ; Collet, C ; Smol, T ; Caumes, R ; Vansenne, F ; Bisulli, F ; Licchetta, L ; Person, R ; Torti, E ; McWalter, K ; Webster, R ; Gerard, EE ; Lesca, G ; Szepetowski, P ; Scheffer, IE ; Mefford, HC ; Carvill, GL (Ovid Technologies (Wolters Kluwer Health), 2023-02-07)
    BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.
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    Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing
    Coppola, A ; Krithika, S ; Iacomino, M ; Bobbili, D ; Balestrini, S ; Bagnasco, I ; Bilo, L ; Buti, D ; Casellato, S ; Cuccurullo, C ; Ferlazzo, E ; Leu, C ; Giordano, L ; Gobbi, G ; Hernandez-Hernandez, L ; Lench, N ; Martins, H ; Meletti, S ; Messana, T ; Nigro, V ; Pinelli, M ; Pippucci, T ; Bellampalli, R ; Salis, B ; Sofia, V ; Striano, P ; Striano, S ; Tassi, L ; Vignoli, A ; Vaudano, AE ; Viri, M ; Scheffer, IE ; May, P ; Zara, F ; Sisodiya, SM (WILEY, 2023-12-13)
    OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM. METHODS: We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder). RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM- subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. SIGNIFICANCE: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM- remains to be elucidated.
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    Aicardi Syndrome Is a Genetically Heterogeneous Disorder
    Ha, TT ; Burgess, R ; Newman, M ; Moey, C ; Mandelstam, SA ; Gardner, AE ; Ivancevic, AM ; Pham, D ; Kumar, R ; Smith, N ; Patel, C ; Malone, S ; Ryan, MM ; Calvert, S ; van Eyk, CL ; Lardelli, M ; Berkovic, SF ; Leventer, RJ ; Richards, LJ ; Scheffer, IE ; Gecz, J ; Corbett, MA (MDPI, 2023-08)
    Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development.
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    Are Germline Mosaic TSC1/2 Variants Present in Controls? Implications for Diagnosis
    Ye, Z ; Lin, S ; Zhao, X ; Wallis, M ; Gao, X ; Sun, L ; Wu, J ; Duan, J ; Yao, Y ; Li, L ; Chen, L ; Cao, D ; Hu, Z ; Zhang, VW ; Berkovic, SF ; Scheffer, IE ; Liao, J ; Hildebrand, MS (ELSEVIER SCIENCE INC, 2024-01)
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    Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study
    D'Gama, AM ; Mulhern, S ; Sheidley, BR ; Boodhoo, F ; Buts, S ; Chandler, NJ ; Cobb, J ; Curtis, M ; Higginbotham, E ; Holland, J ; Khan, T ; Koh, J ; Yliang, NS ; Mcrae, L ; Nesbitt, SE ; Oby, BT ; Paternoster, B ; Patton, A ; Rose, G ; Scotchman, E ; Valentine, R ; Wiltrout, KN ; Hayeems, RZ ; Jain, P ; Lunke, S ; Marshall, CR ; Rockowitz, S ; Sebire, N ; Stark, Z ; White, SM ; Chitty, LS ; Cross, JH ; Scheffer, IE ; Chau, V ; Costain, G ; Poduri, A ; Howell, KB ; McTague, A (ELSEVIER SCIENCE INC, 2023-09)
    BACKGROUND: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. METHODS: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases). INTERPRETATION: Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes. FUNDING: American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre.