Three Steps Novel Machine Learning Method Classifies Uncertain MEFV Gene Variants DOI Creative Commons
Mustafa Tarık Alay, İbrahim Demir, Murat Ki̇ri̇şçi̇

и другие.

Research Square (Research Square), Год журнала: 2023, Номер unknown

Опубликована: Июль 20, 2023

Abstract Introduction: The International Study Group for Systemic Autoinflammatory Diseases (INSAID) consensus criteria revealed that the clinical outcomes of more than half MEFV gene variants are uncertain. In this study, we estabilished a novel approach accurate classification by using optimal number amino acid prediction scores and machine-learning algorithms. Our goal was to determine while also reducing uncertainties. Material-Methods: We extracted from infevers database ,and point mutations were included, others excluded study. then determined in silico instruments our model. On training dataset, implemented seven machine learning algorithms on with known effects. evaluated effectiveness model three steps: First, performed dataset those accuracy greater 90 percent. Second, compared results existing studies. Third, functional level. Results included 266 381 four computational tools algorithm classified Likely pathogenic (LP) an 96.6% classifying 97.6% Benign (LB) variants. Among methods used classify variants, method yielded most datasets. Most predictors LB higher 90% however, LP showed wide range variety between 2% − 62.5%. Disease-causing frequently located domains. Functional level evaluation compatible results. Discussion comparison indicated variant is biggest problem classification, might be candidate solving 96.67% accuracy. Considering 60% effects unresolved, evaluating conjunction manifestations patients significantly simplifies interpretation unknown

Язык: Английский

WONOEP appraisal: Genetic insights into early onset epilepsies DOI Creative Commons
Anne Quatraccioni, Silvia Cases‐Cunillera, Ganna Balagura

и другие.

Epilepsia, Год журнала: 2024, Номер 65(11), С. 3138 - 3154

Опубликована: Сен. 20, 2024

Abstract Early onset epilepsies occur in newborns and infants, to date, genetic aberrations variants have been identified approximately one quarter of all patients. With technological sequencing advances ongoing research, the diagnostic yield for specific seizure disorders is expected increase. Genetic associated with epilepsy include chromosomal abnormalities rearrangements various sizes as well single gene variants. Among these variants, a distinction can be made between germline somatic, latter being increasingly focal cortical malformations recent years. The identification underlying mechanisms syndromes not only revolutionizes schemes but also leads better understanding diseases their interrelationships, ultimately providing new opportunities therapeutic targeting. At XVI Workshop on Neurobiology Epilepsy (WONOEP 2022, Talloires, France, July 2022), etiologies, research models, early were presented discussed.

Язык: Английский

Процитировано

2
Somatic mutation and selection at epidemiological scale DOI Open Access
Andrew Lawson, Federico Abascal, Pantelis Nicola

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Abstract As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations ( 1–10 . Some of these represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding the clonal landscapes human tissues, their impact on risk, disease, remains limited due challenge detecting present in small numbers cells. Here, introduce new version nanorate sequencing (NanoSeq) 11 , duplex method with error rates <5 errors per billion base pairs, which is compatible whole-exome targeted gene sequencing. Deep polyclonal samples single-molecule sensitivity enables simultaneous detection large clones, yielding accurate mutation rates, mutational signatures frequencies any tissue. Applying NanoSeq 1,042 non-invasive oral epithelium 371 blood from twin cohort, found an unprecedentedly rich landscape selection, 49 genes under positive selection driving expansions epithelium, over 62,000 mutations, evidence negative some genes. The high number positively selected multiple provides high-resolution maps across coding non-coding sites, form vivo saturation mutagenesis. Multivariate regression models enable epidemiology studies how carcinogenic exposures risk factors, such as tobacco or alcohol, alter acquisition mutations. Accurate has potential unveil tissue, providing powerful tool study early carcinogenesis, prevention role disease.

Язык: Английский

Процитировано

2
Profiling PIK3CA variants in disorders of somatic mosaicism DOI Creative Commons
Bahareh A. Mojarad, Patricia V. Hernandez,

Michael Evenson

и другие.

Genetics in Medicine Open, Год журнала: 2023, Номер 1(1), С. 100815 - 100815

Опубликована: Янв. 1, 2023

Variants in

Язык: Английский

Процитировано

3
THREE STEPS NOVEL HARD MARGIN ENSEMBLE MACHINE LEARNING METHOD CLASSIFIES UNCERTAINMEFVGENE VARIANTS DOI Open Access
Mustafa Tarık Alay, İbrahim Demir, Murat Ki̇ri̇şçi̇

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Апрель 15, 2023

ABSTRACT Introduction The International Study Group for Systemic Autoinflammatory Diseases (INSAID) consensus criteria revealed that the clinical outcomes of more than half MEFV gene variants are uncertain. We aimed to detect accurate classifications while simultaneously reducing variant uncertainty. Material-Methods extracted from infevers database. then determined optimal number in silico instruments our model. On training dataset, we implemented seven machine learning algorithms on with known effects. evaluated effectiveness model three steps: First, performed machine-learning dataset and those a prediction accuracy greater 90 percent. Second, compared gene-level protein-level results. Finally, results outcomes. Results Our analysis included 266 381 four computational tools (Revel, SIFT, MetaLR, FATHMM). In (RF: 100%, CRAT: KNN: 91%) exceeded threshold value. Thus, contained 134 likely pathogenic (LP) 132 benign (LB) variants. found B30.2 domain were 2.5 times be LP LB (χ2:12.693, p < 0.001, OR: 2.595 [1.532-4.132]. Discussion Considering effects 60% have not yet been determined, combined evaluation methods patients’ manifestations significantly simplifies interpretation unknown

Язык: Английский

Процитировано

1
Evaluating ClinGen variant curation expert panels' application of PVS1 code DOI Creative Commons
Xiaoyan Wang, Haibo Li,

Haiyan Luo

и другие.

European Journal of Medical Genetics, Год журнала: 2024, Номер 67, С. 104909 - 104909

Опубликована: Янв. 8, 2024

The 2015 American College of Medical Genetics and Genomics (ACMG) Association for Molecular Pathology (AMP) guidelines articulates that the effects certain types variants on gene function can often be seen as a complete absence product by leading to lack transcription or nonsense-mediated decay(NMD). However, detailed information considering different loss function(LOF) variants, refined steps assimilating details concerning location variant, changes in strength levels, NMD boundary, any additional pointing true null effect, were all left expert judgement. As part its Clinical Genome Resource (ClinGen) initiative, Variant Curation Expert Panels (VCEPs) are designated make gene/disease-centric specifications accordance with ACMG/AMP guidelines, including more definition what constitutes an appropriate LOF evidence. Our goal was evaluate current developed VCEPs analyse prior curated PVS1 criteria, bringing people occupied genetic data analysis comprehensive understanding this code.

Язык: Английский

Процитировано

0
Evaluation of Bayesian Classification Framework on the Variant Classification of Hereditary Cancer Predisposition Genes DOI Creative Commons
Mohammad K. Eldomery, Jamie L. Maciaszek,

Taylor Cain

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 6, 2024

Abstract Purpose To assess the differences in variant classifications using ACMG/AMP 2015 guidelines and Bayesian point-based classification system (here referred to as point system) 115 hereditary cancer predisposition genes explore utility of sub-tiering. Methods Germline for 721 pediatric patients from an in-house panel were retrospectively evaluated two scoring systems. Results 2376 unique variants identified. The exhibited a lower rate uncertain significance (VUS) ∼15% compared ∼36% (p-value < 0.001). This reduction is attributed likely benign with one supporting evidence (∼12%) or strong (∼4%) system. In addition, resolves conflicting criteria/evidence not recognized by (∼5%). Sub-tiering VUS calls indicates ∼11.5% VUS-Low (0-1 points), while remaining ∼3.5% VUS-Mid (2-3 points) VUS-High (4-5 points). Conclusion reduces facilitates Future large-scale studies are warranted impact on improving reporting and/or clinical management.

Язык: Английский

Процитировано

0
Response to Horta et al DOI

Abbe Lai,

Aubrie Soucy,

Edward Yang

и другие.

Genetics in Medicine, Год журнала: 2024, Номер 26(11), С. 101215 - 101215

Опубликована: Июль 14, 2024

Процитировано

0
Correspondence on “The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2” by Lai et al. DOI

Edgar Horta,

Eric Dahlen, Camille Engel

и другие.

Genetics in Medicine, Год журнала: 2024, Номер 26(11), С. 101214 - 101214

Опубликована: Июль 14, 2024

Язык: Английский

Процитировано

0
Analysis of DNA from brain tissue on stereo-EEG electrodes reveals mosaic epilepsy-related variants DOI
Alissa M. D’Gama, H. Westley Phillips, Yilan Wang

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 22, 2024

Somatic mosaic variants contribute to focal epilepsy, but genetic analysis has been limited patients with drug-resistant epilepsy (DRE) who undergo surgical resection, as the are mainly brain-limited. Stereoelectroencephalography (sEEG) become part of evaluation for many DRE, and sEEG electrodes provide a potential source small amounts brain-derived DNA. We aimed identify, validate, assess distribution potentially clinically relevant in DNA extracted from trace brain tissue on individual electrodes. enrolled prospective cohort eleven pediatric DRE had implanted invasive monitoring, one whom was previously reported. unamplified each electrode also performed whole-genome amplification sample. resected blood/saliva samples where available. deep panel exome sequencing subset case candidate germline variants. validated using amplicon assessed variant allele fraction (VAF) amplified electrode-derived across >150 11 individuals obtained higher concentrations vs Immunohistochemistry confirmed presence neurons Deep demonstrated similar depth coverage between significantly more called samples. In addition

Язык: Английский

Процитировано

0
Neuronal wires and novel epileptic gene studies: Methods and mechanism of brain network and - Recent update DOI
Meenakshi Sundari Rajendran, Rajkumar Prabhakaran,

Rathi Muthaiyan Ahalliya

и другие.

Human Gene, Год журнала: 2023, Номер 37, С. 201186 - 201186

Опубликована: Май 24, 2023

Язык: Английский

Процитировано

0