Publications by authors named "Costin Leu"

Article Synopsis
  • The study explores how copy number variations (CNVs) affect the development of Parkinson's disease (PD), aiming to identify new genetic mechanisms linked to sporadic cases of the disease.
  • Utilizing data from over 11,000 PD patients and nearly 9,000 controls, the researchers discovered 14 significant CNV loci associated with PD, including various gene duplications and deletions.
  • The research highlights a higher prevalence of CNVs in specific PD-related genes among patients and suggests that certain CNVs, especially those involving the gene, may lead to earlier onset of the disease in early-onset PD cases.
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  • * Researchers conducted a large-scale study involving both genetic and non-genetic epilepsy cases from childhood to adolescence, using natural language processing to extract data from electronic health records.
  • * Findings revealed that individuals with genetic epilepsy were diagnosed earlier and had more complex healthcare interactions, especially during the transition from pediatric to adult care, highlighting the need for tailored approaches in their management.
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Objective: Demographic and disease factors are associated with cognitive deficits and postoperative cognitive declines in adults with pharmacoresistant temporal lobe epilepsy (TLE), but the role of genetic factors in cognition in TLE is not well understood. Polygenic scores (PGS) for neurological and neuropsychiatric disorders and IQ have been associated with cognition in patient and healthy populations. In this exploratory study, we examined the relationship between PGS for Alzheimer's disease (AD), depression, and IQ and cognitive outcomes in adults with TLE.

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  • EEM is a generalized epilepsy marked by eyelid myoclonia and other symptoms, showing a potential genetic link which is under investigation.
  • A study involved 105 individuals with EEM, using whole exome sequencing to analyze genetic variants between two groups: those with isolated EEM (EEM-) and those with additional intellectual disabilities or psychiatric disorders (EEM+).
  • Findings revealed that pathogenic variants were predominantly in the CHD2 gene for the EEM+ group, suggesting a stronger genetic association with this subtype, while evidence for a connection in the EEM- group remains inconclusive.
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Focal cortical dysplasia type II (FCDII) is the most common cause of drug-resistant focal epilepsy in children. Herein, we performed a deep histopathology-based genotype-phenotype analysis to further elucidate the clinico-pathological and genetic presentation of FCDIIa compared to FCDIIb. Seventeen individuals with histopathologically confirmed diagnosis of FCD ILAE Type II and a pathogenic variant detected in brain derived DNA whole-exome sequencing or mTOR gene panel sequencing were included in this study.

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  • Carriers of specific genetic variants (1q21.1 distal and 15q11.2 BP1-BP2) show both regional and global brain structure differences compared to noncarriers, but analyzing these differences can be complicated.
  • The study used MRI data from various groups (carriers and noncarriers) to assess how regional brain characteristics diverge from overall brain structure differences.
  • Findings revealed that certain brain regions in carriers exhibited distinct patterns of cortical surface area and thickness that deviated from the global average, suggesting more complex effects of these genetic variants on brain development.
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  • Copy number variants (CNVs) are linked to neurodevelopmental disorders, particularly those involving seizures or epilepsy, prompting researchers to analyze genetic data from large groups of individuals with seizure disorders and epilepsy.
  • The study identified 25 significant genetic loci associated with seizures, of which 22 are newly discovered, including various deletions and duplications at specific chromosomal locations.
  • Further analysis showed connections between these loci and a range of neuropsychiatric conditions, offering insights into the clinical implications of these variants for epilepsy diagnosis and treatment.
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  • Lesional epilepsy is a severe condition often linked to brain malformations like focal cortical dysplasia and hemimegalencephaly, with genetic causes identified through advanced sequencing methods.
  • This review discusses the latest methodological advancements in genetic research related to lesional epilepsy, while also addressing ongoing challenges like detecting low-frequency mutations and validating results.
  • The findings from genetic testing in focal epilepsy can enhance clinical care by aiding in diagnoses, predicting postoperative outcomes, and guiding targeted treatment options.
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Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.

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Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance.

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Variants in monogenic epilepsy genes can cause phenotypes of varying severity. For example, pathogenic variants in the SCN1A gene can cause the severe, sporadic, and drug-resistant Dravet syndrome or the milder familiar GEFS + syndrome. We hypothesized that coding variants in epilepsy-associated genes could lead to other disease-related phenotypes in the general population.

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  • The study investigates the genetic variants in brain tissues from individuals with drug-resistant focal epilepsy, focusing on both tumorous and non-tumorous samples.
  • *It finds that low-grade epilepsy-associated tumors have the highest number of genetic mutations, including more somatic single-nucleotide variants and copy-number variants compared to other conditions like malformations of cortical development and hippocampal sclerosis.
  • *The research highlights specific genes and genetic mechanisms involved in these conditions, suggesting potential targets for improving treatments for epilepsy.
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Background: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified.

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Background: The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with non-familial (sporadic) epilepsies.

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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.

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Article Synopsis
  • - The study investigates how large genetic deletions in monogenic disorders may also impact surrounding loss-of-function (LOF)-intolerant genes, potentially affecting patient symptoms more than previously thought.
  • - Researchers found that 2.5% of deletions associated with haploinsufficiency disorders affect additional LOF-intolerant genes, particularly in individuals with monogenic epilepsy, highlighting the complexity of their phenotypes.
  • - The results suggest that large deletions often involve extra LOF-intolerant genes, indicating a need for further research to better understand their role in monogenic disorders, which could improve treatment strategies.
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  • The study investigates the causes of reduced cortical thickness in human epilepsies using brain imaging and gene expression data to understand underlying mechanisms.* -
  • Researchers found higher levels of activated microglia and endothelial cells in areas of reduced cortical thickness, both in imaging studies and post-mortem brain tissue from epilepsy patients.* -
  • Targeted depletion of activated microglia in a mouse model prevented cortical thinning and neuronal loss, suggesting microglia play a crucial role in these changes, potentially offering new approaches for epilepsy treatment beyond seizure control.*
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  • * SimText offers features for collecting text and extracting relevant words using different text mining methods, along with interactive data analysis and visualization.
  • * The tool is open-source and can be accessed via the Galaxy platform, with additional resources provided for training and a command-line version available on GitHub and Docker.
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Objective: Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.

Methods: Confounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy.

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Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively.

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