SUDEP risk is influenced by longevity genomics: a polygenic risk score study.

Background: Sudden Unexpected Death in Epilepsy (SUDEP) is a rare and tragic outcome in epilepsy, identified by those with the condition as their most serious concern. Although several clinical factors are associated with elevated SUDEP risk, mechanisms underlying SUDEP are poorly understood, making individual risk prediction challenging, especially early in the disease course. We hypothesised that common genetic variation contributes to SUDEP risk.

Cell-type-informed genotyping of mosaic focal epilepsies reveals cell-autonomous and non-cell-autonomous disease-associated transcriptional programs.

While it is widely accepted that somatic variants that activate the PI3K-mTOR pathway are a major cause of drug-resistant focal epilepsy, typically associated with focal cortical dysplasia (FCD) type 2, understanding the mechanism of epileptogenesis requires identifying genotype-associated changes at the single-cell level, which is technically challenging with existing methods. Here, we performed single-nucleus RNA-sequencing (snRNA-seq) of 18 FCD type 2 samples removed surgically for treatment of drug-resistant epilepsy, and 17 non-FCD control samples, and analyzed additional published data comprising >400,000 single nuclei. We also performed simultaneous single-nucleus genotyping and gene expression analysis using two independent approaches: 1) a method that we called genotyping of transcriptomes enhanced with nanopore sequencing (GO-TEN) that combines targeted cDNA long-read sequencing with snRNA-seq, 2) ResolveOME snRNA-seq and DNA genotyping.

Scalable automated reanalysis of genomic data in research and clinical rare disease cohorts.

Reanalysis of genomic data in rare disease is highly effective in increasing diagnostic yields but remains limited by manual approaches. Automation and optimization for high specificity will be necessary to ensure scalability, adoption and sustainability of iterative reanalysis. We developed a publicly available automated tool, Talos, and validated its performance using data from 1,089 individuals with rare genetic disease.

The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series.

Objective: A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss-of-function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders.

Phenotypic Spectrum in Individuals With Pathogenic Loss- and Gain-of-Function Variants.

Background And Objectives: Variants in the gene encoding the γ2 subunit of the γ-aminobutyric acid type A (GABA) receptor are associated with a spectrum of epilepsy phenotypes. These range from simple febrile seizures to more severe conditions, including developmental and epileptic encephalopathies (DEEs). Despite previous analyses suggesting that pathogenic variants may lead to loss-of-function (LoF) receptors, a correlation between functional analysis and clinical phenotypic diversity remains elusive.

Serial correlation between saliva and blood beta-hydroxybutyrate levels in children commencing the ketogenic diet for epilepsy.

Objectives: Accurate and user-friendly methods to measure beta-hydroxybutyrate (BHB) concentration are needed to guide the optimal use of ketogenic diet therapy (KDT). We aimed to determine the correlation between serum, capillary, and salivary BHB concentration, and to validate an electrochemical salivary BHB point-of-care test (POCT) in children commencing KDT for drug-resistant epilepsy.

Methods: This was a single center, prospective cohort study.

Improving genetic diagnostic yield in familial and sporadic cerebral cavernous malformations: detection of copy number and deep Intronic variants.

Cerebral cavernous malformations (CCMs) are intracranial vascular lesions associated with risk of haemorrhages and seizures. While the majority are sporadic and often associated with somatic variants in PIK3CA and MAP3K3, around 20% are familial with germline variants in one of three CCM genes-KRIT1/CCM1, CCM2 and PDCD10/CCM3. We performed comprehensive phenotyping and genetic analysis of nine multiplex families and ten sporadic individuals with CCM.

Understanding speech and language in KIF1A-associated neurological disorder.

KIF1A-associated neurological disorder (KAND) is a genetic condition characterised by motor, cognitive and ophthalmologic features. The speech and language phenotype have not been systematically analysed. Here, we assess speech and language using observer- and clinician-reported outcomes, and performance outcome measures.

Exploring physiological beta-hydroxybutyrate level in children treated with the classical ketogenic diet for drug-resistant epilepsy.

Background: The ketogenic diet (KD) therapy is a primary treatment for drug-resistant epilepsy, and beta-hydroxybutyrate (BHB) is the main ketone produced during KD. However, the pattern of increase in BHB levels is not well understood, and the reference range for BHB need to be defined. The aim of this study was to evaluate the BHB levels in the first three months, especially one week, after KD initiation, and to explore the physiological reference range for BHB.

Identifying individuals with rare disease variants by inferring shared ancestral haplotypes from SNP array data.

We describe FoundHaplo, an identity-by-descent algorithm that can be used to screen untyped disease-causing variants using single nucleotide polymorphism (SNP) array data. FoundHaplo leverages knowledge of shared disease haplotypes for inherited variants to identify those who share the disease haplotype and are, therefore, likely to carry the rare [minor allele frequency (MAF) ≤ 0.01%] variant.

Optical genome mapping enables accurate testing of large repeat expansions.

Short tandem repeats (STRs) are common variations in human genomes that frequently expand or contract, causing genetic disorders, mainly when expanded. Traditional diagnostic methods for identifying these expansions, such as repeat-primed PCR and Southern blotting, are often labor-intensive, locus-specific, and are unable to precisely determine long repeat expansions. Sequencing-based methods, although capable of genome-wide detection, are limited by inaccuracy (short-read technologies) and high associated costs (long-read technologies).

Variants in ATP6V0C are associated with Dravet-like developmental and epileptic encephalopathy.

Objective: Dravet syndrome (DS) is a developmental and epileptic encephalopathy. Diagnosis is clinical, but ~90% of patients have pathogenic variants in SCN1A. ATP6V0C has recently been proposed as a novel candidate gene for epilepsy, with or without developmental delay.

Long-term safety and effectiveness of fenfluramine in children and adults with Dravet syndrome.

Objective: We analyzed the long-term safety and effectiveness of fenfluramine (FFA) in patients with Dravet syndrome (DS) in an open-label extension (OLE) study after participating in randomized controlled trials (RCTs) or commencing FFA de novo as adults.

Methods: Patients with DS who participated in one of three RCTs or were 19 to 35 years of age and started FFA de novo were included. Key endpoints were: incidence of treatment-emergent adverse events (TEAEs) in the safety population, and median percentage change in monthly convulsive seizure frequency (MCSF) from the RCT baseline to end of study (EOS) in the modified intent-to-treat (mITT) population.

International Precision Child Health Partnership (IPCHiP): an initiative to accelerate discovery and improve outcomes in rare pediatric disease.

Advances in genomic technologies have revolutionized the diagnosis of rare genetic diseases, leading to the emergence of precision therapies. However, there remains significant effort ahead to ensure the promise of precision medicine translates to improved outcomes. Here, we discuss the challenges in advancing precision child health and highlight how international collaborations such as the International Precision Child Health Partnership, which embed research into clinical care, can maximize benefits for children globally.

Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials.

Developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies, characterized by drug-resistant seizures and developmental slowing or regression. DEEs encompass many epilepsy syndromes, although not all patients with a DEE can be classified into a specific syndrome. Our understanding of the etiologies of DEEs has been revolutionized with next-generation sequencing, with more than 900 genes implicated, in addition to structural causes.

Psychoses of Epilepsy: Unravelling the Phenotypic and Genotypic Features.

Objectives: We analyzed the genotypic and phenotypic features of patients with psychosis of epilepsy (POE).

Methods: Patients with POE recruited to an epilepsy genetics research program underwent phenotyping and genetic analysis. The latter included screening for rare pathogenic variants in epilepsy genes, and polygenic risk score (PRS) calculation for common risk variants associated with schizophrenia.

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.

Fulfilling the needs of caregivers in delivering health services to children with developmental and epileptic encephalopathies.

Introduction: Patients with developmental and epileptic encephalopathies (DEEs) have multiple comorbidities and high healthcare needs. Whether health services meet the needs of this patient population and their families is not well understood. We explored caregiver perspectives on their child's health service use, satisfaction with health services, and priorities for improvement.

Speech, Language and Non-verbal Communication in CLN2 and CLN3 Batten Disease.

CLN2 and CLN3 diseases, the most common types of Batten disease (also known as neuronal ceroid lipofuscinosis), are childhood dementias associated with progressive loss of speech, language and feeding skills. Here we delineate speech, language, non-verbal communication and feeding phenotypes in 33 individuals (19 females) with a median age of 9.5 years (range 3-28 years); 16 had CLN2 and 17 CLN3 disease; 8/15 (53%) participants with CLN2 and 8/17 (47%) participants with CLN3 disease had speech and language impairments prior to genetic diagnosis.

Constitutive opening of the Kv7.2 pore activation gate causes -developmental encephalopathy.

Pathogenic variants in encoding Kv7.2 voltage-gated potassium channel subunits cause developmental encephalopathies (-encephalopathies), both with and without epilepsy. We herein describe the clinical, in vitro, and in silico features of two encephalopathy-causing variants (A317T, L318V) in Kv7.

Eating habits and behaviors in children with Dravet syndrome: A case-control study.

This study evaluated food preferences and eating behaviors of individuals with Dravet syndrome. Patients diagnosed with Dravet syndrome were recruited, as well as a control group composed of siblings of patients with epilepsy (any form). The Food Preference Questionnaire and the Child Eating Behavior Questionnaire were completed by caregivers along with two open-ended questions regarding eating challenges.