The landscape of tolerated genetic variation in humans and primates

Science, Год журнала: 2023, Номер 380(6648)

Опубликована: Июнь 1, 2023

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding their clinical relevance remains largely incomplete. To systematically decipher the effects human variants, we obtained whole-genome data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these can be inferred to have nondeleterious humans based on presence at high allele frequencies other populations. use this resource classify 6% all possible as likely benign impute pathogenicity remaining 94% deep learning, achieving state-of-the-art accuracy diagnosing pathogenic patients diseases.

Язык: Английский

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Insights on variant analysis in silico tools for pathogenicity prediction

Frontiers in Genetics, Год журнала: 2022, Номер 13

Опубликована: Ноя. 29, 2022

Molecular biology is currently a fast-advancing science. Sequencing techniques are getting cheaper, but the interpretation of genetic variants requires expertise and computational power, therefore still challenge. Next-generation sequencing releases thousands to classify them, researchers propose protocols with several parameters. Here we present review in silico pathogenicity prediction tools involved variant prioritization/classification process used by some international for analysis studies evaluating their efficiency.

Язык: Английский

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Liquid Biopsy of Cerebrospinal Fluid Enables Selective Profiling of Glioma Molecular Subtypes at First Clinical Presentation

Clinical Cancer Research, Год журнала: 2023, Номер 29(7), С. 1252 - 1266

Опубликована: Янв. 17, 2023

Abstract Purpose: Current glioma diagnostic guidelines call for molecular profiling to stratify patients into prognostic and treatment subgroups. In case the tumor tissue is inaccessible, cerebrospinal fluid (CSF) has been proposed as a reliable DNA source liquid biopsy. We prospectively investigated use of CSF characterization newly diagnosed gliomas. Experimental Design: recruited two cohorts with glioma, one (n = 45) providing collected in proximity tumor, other 39) by lumbar puncture (LP). Both provided tissues surgery concomitant sampling. samples retrieved from matched tumors were systematically characterized compared comprehensive (NGS, next-generation sequencing) or targeted (ddPCR, droplet digital PCR) methodologies. Conventional diagnosis outcomes compared. Results: report that abundant close but scanty mostly below NGS sensitivity threshold LP. Indeed, released cells invading liquoral spaces, generating gradient attenuates departing tumor. Nevertheless, >60% LP samples, sufficient assess selected panel genetic alterations (IDH TERT promoter mutations, EGFR amplification, CDKN2A/B deletion: ITEC protocol) MGMT methylation that, combined imaging, enable tissue-agnostic identification main subtypes. Conclusions: This study shows potentialities limitations biopsy achieving gliomas at first clinical presentation proposes protocol maximize information retrievable DNA.

Язык: Английский

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Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Март 4, 2024

Abstract The giant protein titin (TTN) is a sarcomeric that forms the myofibrillar backbone for components of contractile machinery which plays crucial role in muscle disorders and cardiomyopathies. Diagnosing TTN pathogenic variants has important implications patient management genetic counseling. Genetic testing can help identify individuals at risk developing cardiomyopathies, allowing early intervention personalized treatment strategies. Furthermore, identifying inform prognosis guide therapeutic decisions. Deciphering intricate genotype–phenotype correlations between their pathologic traits cardiomyopathies imperative gene-based diagnosis, assessment, clinical management. With increasing use next-generation sequencing (NGS), high number gene have been detected patients with However, not all cardiomyopathy cohorts be assumed to disease-causing. interpretation remains challenging due background population variation. This narrative review aimed comprehensively summarize current evidence on identified published studies determine specific are likely contributors development.

Язык: Английский

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Elucidating the link between thyroid cancer and mercury exposure: a review and meta-analysis

Environmental Science and Pollution Research, Год журнала: 2024, Номер 31(9), С. 12841 - 12855

Опубликована: Янв. 26, 2024

Abstract Mercury (Hg) is a widely distributed and bioavailable metal of public health concern, with many known human toxicities, but data regarding mercury's influence on thyroid cancer (TC) scarce. to impact several molecular pathways implicated in carcinogenesis, its proclivity for bioaccumulation the suggests potential modulatory effect. We conducted literature/systematic review studies between 1995–2022 intending define better establish relationships these two entities, congregate evidence role identify populations interest further study. Insufficient precludes definitive conclusions dietary mercury as TC risk factor; however, common mechanisms affected by are crucial development, including biochemical, endocrine, reactive oxygen species effects. Quantitative analysis revealed associations exposure. In three studies, average urine levels were higher patients, mean difference 1.86 µg/g creatinine (95% CI = 0.32–3.41). investigating exposure elevated levels, exposed group exhibited developing TC, relative 1.90 1.76–2.06). tissue (ppm) averaging 0.14 (0.06–0.22) cancerous cases (N 178) 0.08 (0.04–0.11) normal thyroids 257). Our findings suggest an association risk, implying possible predisposing factor. Further research necessary reveal clinical relevance environmental exposures pathogenesis.

Язык: Английский

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Somatic DNA Variants in Epilepsy Surgery Brain Samples from Patients with Lesional Epilepsy

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 815 - 815

Опубликована: Янв. 19, 2025

Epilepsy affects 50 million people worldwide and is drug-resistant in approximately one-third of cases. Even when a structural lesion identified as the epileptogenic focus, understanding underlying genetic causes crucial to guide both counseling treatment decisions. Both somatic germline DNA variants may contribute itself and/or influence severity symptoms. We therefore used whole exome sequencing (WES) search for potentially pathogenic brain samples from children with lesional epilepsy who underwent surgery. WES was performed on 20 paired extracted tissue reference same patient, such leukocytes or fibroblasts. The data were jointly analyzed using GATK Mutect2 identify single nucleotide (SNVs) insertions/deletions (InDels), which subsequently evaluated silico their disease-causing potential MutationTaster2021. known five patients (25%) variant allele frequencies (VAF) ranging 3–35% genes MTOR, TSC2, PIK3CA, FGFR1, PIK3R1 cortical malformations central nervous system (CNS) tumors. Depending VAF, we different methods Sanger sequencing, allele-specific qPCR, targeted ultra-deep (amplicon sequencing) confirm variant. In contrast usually straightforward confirmation variants, validation more challenging because current have limitations sensitivity, specificity, cost-effectiveness. our study, additional candidates VAFs 0.7–7.0% that could not be validated by an orthogonal method. This highlights importance validation, especially those very low frequencies.

Язык: Английский

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FABIAN-variant: predicting the effects of DNA variants on transcription factor binding

Nucleic Acids Research, Год журнала: 2022, Номер 50(W1), С. W322 - W329

Опубликована: Май 6, 2022

While great advances in predicting the effects of coding variants have been made, assessment non-coding remains challenging. This is especially problematic for within promoter regions which can lead to over-expression a gene or reduce even abolish its expression. The binding transcription factors DNA be predicted using position weight matrices (PWMs). More recently, factor flexible models (TFFMs) introduced and shown more accurate than PWMs. TFFMs are based on hidden Markov account complex positional dependencies. Our new web-based application FABIAN-variant uses 1224 3790 PWMs predict whether degree affect 1387 different human factors. For each variant factor, software combines results final prediction resulting binding-affinity change. written C++ speed but entered through web interface. Alternatively, VCF file uploaded assess identified by high-throughput sequencing. search restricted vicinity candidate genes. available freely at https://www.genecascade.org/fabian/.

Язык: Английский

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Computational approaches for predicting variant impact: An overview from resources, principles to applications

Frontiers in Genetics, Год журнала: 2022, Номер 13

Опубликована: Сен. 29, 2022

One objective of human genetics is to unveil the variants that contribute diseases. With rapid development and wide use next-generation sequencing (NGS), massive genomic sequence data have been created, making personal genetic information available. Conventional experimental evidence critical in establishing relationship between phenotype but with low efficiency. Due lack comprehensive databases resources which present clinical on genotype-phenotype relationship, as well accumulating found from NGS, different computational tools can predict impact greatly developed bridge gap. In this review, we a brief introduction discussion about approaches for variant prediction. Following an innovative manner, mainly focus non-synonymous (nsSNVs) prediction categorize them into six classes. Their underlying rationale constraints, together concerns remedies raised comparative studies are discussed. We also how predictive employed research. Although diverse constraints exist, indispensable exploring relationship.

Язык: Английский

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Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

Orphanet Journal of Rare Diseases, Год журнала: 2024, Номер 19(1)

Опубликована: Фев. 6, 2024

Abstract Background Neurodevelopmental disorders (NDDs) and/or associated multiple congenital abnormalities (MCAs) represent a genetically heterogeneous group of conditions with an adverse prognosis for the quality intellectual and social abilities common daily functioning. The rapid development exome sequencing (ES) techniques, together trio-based analysis, nowadays leads to up 50% diagnostic yield. Therefore, it is considered as state-of-the-art approach in these diagnoses. Results In our study, we present results ES cohort 85 families 90 children severe NDDs MCAs. interconnection in-house bioinformatic pipeline unique algorithm variant prioritization resulted yield 48.9% (44/90), including rare novel causative variants (41/90) intragenic copy-number variations (CNVs) (3/90). Of total number 47 variants, 53.2% (25/47) were novel, highlighting clinical benefit unexplained NDDs. Moreover, was verified reliable tool detection CNVs, ranging from exon deletions ( GRIN2A, ZC4H2 genes) 6-Mb duplication. functional analysis using PANTHER Gene Ontology confirmed involvement genes wide spectrum developmental processes molecular pathways, which form essential structural components central nervous system. Conclusion Taken together, one first studies this scale European region. Based on high paediatric 48.9%, confirm effective first-tier test genetic evaluation

Язык: Английский

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Pivotal role of BCL11B in the immune, hematopoietic and nervous systems: a review of the BCL11B-associated phenotypes from the genetic perspective

Genes and Immunity, Год журнала: 2024, Номер 25(3), С. 232 - 241

Опубликована: Март 12, 2024

The transcription factor BCL11B plays an essential role in the development of central nervous system and T cell differentiation by regulating expression numerous genes involved several pathways. Monoallelic defects gene leading to loss-of-function are associated with a wide spectrum phenotypes, including neurological disorders or without immunological features susceptibility hematological malignancies. From genetic point view, landscape mutations reported so far does not fully explain genotype-phenotype correlation. In this review, we sought compile phenotypic genotypic variables previously order provide better understanding consequences deleterious variants. We also highlight importance careful evaluation mutation type, its location pattern inheritance variants assign most accurate pathogenicity actionability findings.

Язык: Английский

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