Novel biallelic variants affect the nuclear pore complex and expand the clinical spectrum to include brain malformations.

Biallelic variants in cause isolated or syndromic steroid-resistant nephrotic syndrome (SRNS), characterised by proteinuria, hypoalbuminaemia and focal segmental glomerulosclerosis that progresses to end-stage renal disease. Patients with syndromic SRNS have microcephaly, developmental delay or intellectual disability and short stature. Simplified gyration is observed in some individuals.

SCN1A pathogenic variants do not have a distinctive blood-derived DNA methylation signature.

DNA methylation signatures ("episignatures") can be used as biomarkers of genetic aberrations, clinical phenotypes, and environmental exposures in rare diseases. Episignatures are utilized in molecular diagnostics and can clarify variants of uncertain significance. A growing number of disease genes, including epilepsy genes, exhibit robust and reproducible episignatures.

Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome.

Pathogenic heterozygous variants in CHD4 cause Sifrim-Hitz-Weiss syndrome, a neurodevelopmental disorder associated with brain anomalies, heart defects, macrocephaly, hypogonadism, and additional features with variable expressivity. Most individuals have non-recurrent missense variants, complicating variant interpretation. A few were reported with truncating variants, and their role in disease is unclear.

Trauma, coping, and adjustment when parenting a child with Dravet syndrome.

Objectives: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy that requires significant caregiver input across the lifespan. This predominantly falls on parents, who are faced with considerable challenges including physical demands, financial burdens, and sustained pressure on mental wellbeing leading to mental health difficulties. We aimed to develop a grounded theory model for the process of coping and adjustment that occurs when caring for a child who has a diagnosis of DS.

Caregiver burden and therapeutic needs in Dravet syndrome - A national UK cross-sectional questionnaire study.

Background And Objectives: Dravet Syndrome is a severe developmental and epileptic encephalopathy with significant care needs for affected individuals and families. Our objective was to characterise the caregiver burden and therapeutic needs of families caring for an individual with Dravet Syndrome from child to adulthood, to examine age related differences in co-morbidities, and identify current gaps in health and social care.

Methods: Cross-sectional national survey conducted by the patient advocacy group Dravet Syndrome UK (DSUK) emailed to registered families caring for an individual with a confirmed diagnosis of Dravet syndrome.

POLR3B is associated with a developmental and epileptic encephalopathy with myoclonic-atonic seizures and ataxia.

Objective: POLR3B encodes the second largest subunit of RNA polymerase III, which is essential for transcription of small non-coding RNAs. Biallelic pathogenic variants in POLR3B are associated with an inherited hypomyelinating leukodystrophy. Recently, de novo heterozygous variants in POLR3B were reported in six individuals with ataxia, spasticity, and demyelinating peripheral neuropathy.

Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D/EE-SWAS).

Objective: To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS).

Methods: All patients fulfilled International League Against Epilepsy (ILAE) DEE-SWAS or EE-SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed.

Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies.

Objective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood.

Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies.

Long-term predictors of developmental outcome and disease burden in -positive Dravet syndrome.

Dravet syndrome is a severe infantile onset developmental and epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene . Prospective data on long-term developmental and clinical outcomes are limited; this study seeks to evaluate the clinical course of Dravet syndrome over a 10-year period and identify predictors of developmental outcome. mutation-positive Dravet syndrome patients were prospectively followed up in the UK from 2010 to 2020.

POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies.

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects.

Rates, causes and predictors of all-cause and avoidable mortality in 163 686 children and young people with and without intellectual disabilities: a record linkage national cohort study.

Objectives: To investigate mortality rates and associated factors, and avoidable mortality in children/young people with intellectual disabilities.

Design: Retrospective cohort; individual record-linked data between Scotland's 2011 Census and 9.5 years of National Records for Scotland death certification data.

GIGYF1 disruption associates with autism and impaired IGF-1R signaling.

Autism spectrum disorder (ASD) represents a group of neurodevelopmental phenotypes with a strong genetic component. An excess of likely gene-disruptive (LGD) mutations in GIGYF1 was implicated in ASD. Here, we report that GIGYF1 is the second-most mutated gene among known ASD high-confidence risk genes.

Gene variant effects across sodium channelopathies predict function and guide precision therapy.

Pathogenic variants in the voltage-gated sodium channel gene family lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect.

Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants.

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials.

Infantile spasms: Etiology, lead time and treatment response in a resource limited setting.

This study explores the etiology and lead time to treatment for infantile spasm (IS) patients and their effect on treatment responsiveness, in a limited resource setting. Patients with IS onset age ≤12 months', seen over 3 years were recruited retrospectively. Clinical information, neuroimaging and genetic results retrieved.

Neuronal antibody prevalence in children with seizures under 3 years: A prospective national cohort.

Objective: To report the prevalence of anti-neuronal antibodies in a prospective whole-nation cohort of children presenting with seizures before their third birthday.

Methods: This was a prospective population-based national cohort study involving all children presenting with new-onset epilepsy or complex febrile seizures before their third birthday over a 3-year period. Patients with previously identified structural, metabolic, or infectious cause for seizures were excluded.

Epilepsy and developmental disorders: Next generation sequencing in the clinic.

Background: The advent of Next Generation Sequencing (NGS) has led to a redefining of the genetic landscape of the epilepsies. Hundreds of single gene epilepsies have been described. Genes associated with epilepsy involve diverse processes.

SCN1A variants from bench to bedside-improved clinical prediction from functional characterization.

Variants in the SCN1A gene are associated with a wide range of disorders including genetic epilepsy with febrile seizures plus (GEFS+), familial hemiplegic migraine (FHM), and the severe childhood epilepsy Dravet syndrome (DS). Predicting disease outcomes based on variant type remains challenging. Despite thousands of SCN1A variants being reported, only a minority has been functionally assessed.

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

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.

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities.