Conserved missense variant pathogenicity and correlated phenotypes across paralogous genes.

Background: The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Prior research shows that the deleterious effects and the subsequent molecular consequences of variants are often conserved among paralogous protein sequences within a gene family. Here, we systematically quantify on an exome-wide scale whether the existence of pathogenic variants in paralogous genes at a conserved position can serve as evidence for the pathogenicity of a new variant.

SCN9A should not be considered an epilepsy gene; Refuting a gene-disease association.

Objective: The SCN9A gene is primarily expressed in nociceptive pathways within the peripheral nervous system, and pathogenic variants are associated with human pain disorders. In recent years, several studies have proposed SCN9A as a monogenic cause of epilepsy. Our objective was to critically appraise the SCN9A-epilepsy gene-disease relationship.

Genome-wide assessment identifies novel runs of homozygosity linked to Parkinson's disease etiology across diverse ancestral populations.

Objective: We conducted the first large-scale, multi-ancestral investigation of Parkinson's disease (PD) to examine the impact of genome-wide homozygosity on disease risk and age at onset. Using genotyping, imputed, and whole-genome sequencing (WGS) data from 16,599 PD cases and 13,585 controls across nine ancestral populations from the Global Parkinson's Genetics Program, we aimed to identify novel regions of homozygosity contributing to PD heritability.

Methods: We analyzed runs of homozygosity (ROHs) for total length (S), number (N), average length (AV), and genomic inbreeding coefficient (F).

Polygenic score analysis identifies distinct genetic risk profiles in Alzheimer's disease comorbidities.

Alzheimer's disease (AD) is usually accompanied by comorbidities such as type 2 diabetes (T2D), epilepsy, major depressive disorder (MDD), and migraine headaches (MH) that can significantly affect patient management and progression. As AD, these comorbidities have their own cumulative common genetic risk component that can be explored in a single individual through polygenic scores. Utilizing data from the UK Biobank, we investigated the correlation between polygenic scores (PGS) for these comorbidities and their actual presentation in AD patients.

Psychiatric genetics in the diverse landscape of Latin American populations.

Psychiatric disorders are highly heritable and polygenic, influenced by environmental factors and often comorbid. Large-scale genome-wide association studies (GWASs) through consortium efforts have identified genetic risk loci and revealed the underlying biology of psychiatric disorders and traits. However, over 85% of psychiatric GWAS participants are of European ancestry, limiting the applicability of these findings to non-European populations.

Evaluating novel in silico tools for accurate pathogenicity classification in epilepsy-associated genetic missense variants.

Objective: Determining the pathogenicity of missense variants in clinical genetic tests for individuals with epilepsy is crucial for guiding personalized treatment. However, achieving a definitive pathogenic classification remains challenging, with most missense variants still classified as variants of uncertain significance (VUS) and with the availability of many computational tools which may provide conflicting predictions. Here, we aim to evaluate the performance of state-of-the-art computational tools in pathogenicity prediction of missense variants in epilepsy-associated genes.

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.

SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.

CNV-ClinViewer: enhancing the clinical interpretation of large copy-number variants online.

Motivation: Pathogenic copy-number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts.

Quantitative Phenotype Morbidity Description of -Associated Syndrome.

Characterized by developmental delay with severe speech delay, dental anomalies, cleft palate, skeletal abnormalities, and behavioral difficulties, -associated syndrome (SAS) is caused by pathogenic variants in . The SAS phenotype range of severity has been documented previously in large series. Using data from the SAS registry, we present the SAS severity score, a comprehensive scoring rubric that encompasses 15 different individual neurodevelopmental and systemic features.

Data-driven historical characterization of epilepsy-associated genes.

Many epilepsy-associated genes have been identified over the last three decades, revealing a remarkable molecular heterogeneity with the shared outcome of recurrent seizures. Information about the genetic landscape of epilepsies is scattered throughout the literature and answering the simple question of how many genes are associated with epilepsy is not straightforward. Here, we present a computationally driven analytical review of epilepsy-associated genes using the complete scientific literature in PubMed.

Delineation of functionally essential protein regions for 242 neurodevelopmental genes.

Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial.

Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes.

Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. As a consequence, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion-channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated.

The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3.

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies.

This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes.

Incidence and prevalence of major epilepsy-associated brain lesions.

Epilepsy surgery is an effective treatment option for drug-resistant focal epilepsy patients with associated structural brain lesions. However, little epidemiological data are available regarding the number of patients with these lesions. We reviewed data regarding (1) the prevalence and incidence of epilepsy; (2) the proportion of epilepsy patients with focal epilepsy, drug-resistant epilepsy, and drug-resistant focal epilepsies; and (3) the number of epilepsy presurgical evaluations and surgical resections.

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.

Analysing an allelic series of rare missense variants of CACNA1I in a Swedish schizophrenia cohort.

CACNA1I is implicated in the susceptibility to schizophrenia by large-scale genetic association studies of single nucleotide polymorphisms. However, the channelopathy of CACNA1I in schizophrenia is unknown. CACNA1I encodes CaV3.

Structural mapping of GABRB3 variants reveals genotype-phenotype correlations.

Purpose: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations.

Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases.

Current knowledge of SLC6A1-related neurodevelopmental disorders.

Advances in gene discovery have identified genetic variants in the solute carrier family 6 member 1 gene as a monogenic cause of neurodevelopmental disorders, including epilepsy with myoclonic atonic seizures, autism spectrum disorder and intellectual disability. The solute carrier family 6 member 1 gene encodes for the GABA transporter protein type 1, which is responsible for the reuptake of the neurotransmitter GABA, the primary inhibitory neurotransmitter in the central nervous system, from the extracellular space. GABAergic inhibition is essential to counterbalance neuronal excitation, and when significantly disrupted, it negatively impacts brain development leading to developmental differences and seizures.