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Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59; p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females (OR = 1.19, p = 0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.

Sleep problems in children with epilepsy (CWE) are common. However, little is known about parental experiences and feelings about managing sleep in their CWE. To provide the most appropriate services' provision, it is essential that the lived experience of parents of this patient group and the issues and problems that they face in managing their child's sleep is understood. In 2018, nine mothers of CWE (aged 5-15 years) were interviewed about their perceptions and experiences around their child's sleep, sleep problems and their management, the impact of sleep difficulties on the child and their family and available support. Four themes were identified that represented the nature of the child's sleep problems, including settling and night-waking issues, parasomnias and child anxiety around sleep. Seven themes represented mothers' experiences of managing their child's sleep and any associated problems, including the longstanding challenging nature of child sleep issues, management strategies adopted, challenges related to managing sleep over time, the link between sleep and seizures, the negative impact of poor sleep on daytime functioning, role of antiseizure medication and maternal concerns about child sleep. One theme represented the perceived lack of information, help and support available. Findings suggest there are unmet needs in supporting parents to deal with sleep, sleep problems and their management in CWE. This individual study was conducted under the umbrella of the CASTLE research programme (see https://castlestudy.org.uk/). Parents who have lived experience of parenting a child with epilepsy were co-applicants for the programme and were involved in the original conception, aims, design and funding application for the research programme (including the project reported in this paper) and advised on project design. Mothers of CWE who have lived experience of managing sleep and sleep problems in their child were participants who shared their experiences through the interviews, which formed the data of the current study.

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p  < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p  = 0.001) and females (OR = 3.0, p  < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p  = 0.001), absence seizures (OR = 6.0, p  < 0.001) and stress-precipitated seizures (OR = 5.3, p  = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p  = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation.

IntroductionThe prevalence of mental health symptoms in people with epilepsy (PWE) is elevated compared with that of the general population. These symptoms can negatively impact epilepsy management and patient outcomes but can be treated once recognised. It is, therefore, important to screen for these symptoms to identify needs and put in place appropriate support. Unfortunately, mental health symptoms are rarely addressed in epilepsy services due to time constraints, lack of resources and communication between psychological and medical professionals. These barriers can result in diagnostic overshadowing, where symptoms may be attributed to the disease and reduce the level of support PWE receive. Implementing an online screening tool embedded in the electronic health record (EHR) platform with supported referral pathways may remove some of these barriers.Methods and analysisWe will follow the Integrating Mental and Physical Healthcare: Research Training and Services framework, which is a routine clinical data collection tool used by clinical teams to electronically screen psychological symptoms among patients with long-term physical health conditions. Patient outcomes including mental health, physical health and psychosocial outcomes will be collected and uploaded to the EHR platform in real-time. An appropriate referral pathway will be recommended depending on severity of the outcome scores. We will initially pilot the tool for individuals aged 13 years and above through epilepsy clinics at King’s College Hospital. Following this, the acceptability and feasibility of the tool will be assessed at baseline, 6 and 12 months.Ethics and disseminationEthics approval was obtained from the National Health Service Research Ethics Committee of South Central—Oxford C, reference: 21/EM/0205. This study is expected to inform the use of integrated electronic mental health screening for youth in epilepsy clinics and improve access to psychological support. The findings will be disseminated through academic peer-reviewed journals, poster presentations and scientific meetings.

Purpose To provide a detailed electroclinical description and expand the phenotype of PIGT-CDG, to perform genotype–phenotype correlation, and to investigate the onset and severity of the epilepsy associated with the different genetic subtypes of this rare disorder. Furthermore, to use computer-assisted facial gestalt analysis in PIGT-CDG and to the compare findings with other glycosylphosphatidylinositol (GPI) anchor deficiencies. Methods We evaluated 13 children from eight unrelated families with homozygous or compound heterozygous pathogenic variants in PIGT . Results All patients had hypotonia, severe developmental delay, and epilepsy. Epilepsy onset ranged from first day of life to two years of age. Severity of the seizure disorder varied from treatable seizures to severe neonatal onset epileptic encephalopathies. The facial gestalt of patients resembled that of previously published PIGT patients as they were closest to the center of the PIGT cluster in the clinical face phenotype space and were distinguishable from other gene-specific phenotypes. Conclusion We expand our knowledge of PIGT . Our cases reaffirm that the use of genetic testing is essential for diagnosis in this group of disorders. Finally, we show that computer-assisted facial gestalt analysis accurately assigned PIGT cases to the multiple congenital anomalies–hypotonia–seizures syndrome phenotypic series advocating the additional use of next-generation phenotyping technology.

Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genome-wide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine mapping CTS to variants in Elongator Protein Complex 4 ( ELP4) in two independent data sets; the strongest evidence was with rs986527 in intron 9 of ELP4 , providing a likelihood ratio of 629:1 ( P =0.0002) in favor of an association. Resequencing of ELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of ELP4 . ELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.

Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel Na V 1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo , and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the Na V 1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of Na V 1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A -associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

We evaluated a new epilepsy genetic diagnostic and counseling service covering a UK population of 3.5 million. We calculated diagnostic yield, estimated clinical impact, and surveyed referring clinicians and families. We costed alternative investigational pathways for neonatal onset epilepsy. Patients with epilepsy of unknown aetiology onset < 2 years; treatment resistant epilepsy; or familial epilepsy were referred for counseling and testing. We developed NGS panels, performing clinical interpretation with a multidisciplinary team. We held an educational workshop for paediatricians and nurses. We sent questionnaires to referring paediatricians and families. We analysed investigation costs for 16 neonatal epilepsy patients. Of 96 patients, a genetic diagnosis was made in 34% of patients with seizure onset < 2 years, and 4% > 2 years, with turnaround time of 21 days. Pathogenic variants were seen in SCN8A, SCN2A, SCN1A, KCNQ2, HNRNPU, GRIN2A, SYNGAP1, STXBP1, STX1B, CDKL5, CHRNA4, PCDH19 and PIGT. Clinician prediction was poor. Clinicians and families rated the service highly. In neonates, the cost of investigations could be reduced from £9362 to £2838 by performing gene panel earlier and the median diagnostic delay of 3.43 years reduced to 21 days. Panel testing for epilepsy has a high yield among children with onset < 2 years, and an appreciable clinical and financial impact. Parallel gene testing supersedes single gene testing in most early onset cases that do not show a clear genotype-phenotype correlation. Clinical interpretation of laboratory results, and in-depth discussion of implications for patients and their families, necessitate multidisciplinary input and skilled genetic counseling.

IntroductionSleep and epilepsy have an established bidirectional relationship yet only one randomised controlled clinical trial has assessed the effectiveness of behavioural sleep interventions for children with epilepsy. The intervention was successful, but was delivered via face-to-face educational sessions with parents, which are costly and non-scalable to population level. The Changing Agendas on Sleep, Treatment and Learning in Epilepsy (CASTLE) Sleep-E trial addresses this problem by comparing clinical and cost-effectiveness in children with Rolandic epilepsy between standard care (SC) and SC augmented with a novel, tailored parent-led CASTLE Online Sleep Intervention (COSI) that incorporates evidence-based behavioural components.Methods and analysesCASTLE Sleep-E is a UK-based, multicentre, open-label, active concurrent control, randomised, parallel-group, pragmatic superiority trial. A total of 110 children with Rolandic epilepsy will be recruited in outpatient clinics and allocated 1:1 to SC or SC augmented with COSI (SC+COSI). Primary clinical outcome is parent-reported sleep problem score (Children’s Sleep Habits Questionnaire). Primary health economic outcome is the incremental cost-effectiveness ratio (National Health Service and Personal Social Services perspective, Child Health Utility 9D Instrument). Parents and children (≥7 years) can opt into qualitative interviews and activities to share their experiences and perceptions of trial participation and managing sleep with Rolandic epilepsy.Ethics and disseminationThe CASTLE Sleep-E protocol was approved by the Health Research Authority East Midlands (HRA)–Nottingham 1 Research Ethics Committee (reference: 21/EM/0205). Trial results will be disseminated to scientific audiences, families, professional groups, managers, commissioners and policymakers. Pseudo-anonymised individual patient data will be made available after dissemination on reasonable request.Trial registration numberISRCTN13202325.