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结合多重功能数据以改善变异分类。

Combining multiplexed functional data to improve variant classification.

作者信息

Calhoun Jeffrey D, Dawood Moez, Rowlands Charlie F, Fayer Shawn, Radford Elizabeth J, McEwen Abbye E, Turnbull Clare, Spurdle Amanda B, Starita Lea M, Jagannathan Sujatha

机构信息

Ken and Ruth Davee Department of Neurology, Northwestern Feinberg School of Medicine, Chicago, Illinois.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

出版信息

ArXiv. 2025 Mar 24:arXiv:2503.18810v1.


DOI:
PMID:40196145
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11975307/
Abstract

With the surge in the number of variants of uncertain significance (VUS) reported in ClinVar in recent years, there is an imperative to resolve VUS at scale. Multiplexed assays of variant effect (MAVEs), which allow the functional consequence of 100s to 1000s of genetic variants to be measured in a single experiment, are emerging as a source of evidence which can be used for clinical gene variant classification. Increasingly, there are multiple published MAVEs for the same gene, sometimes measuring different aspects of variant impact. Where multiple functional consequences may need to be considered to get a more complete understanding of variant effects for a given gene, combining data from multiple MAVEs may lead to the assignment of increased evidence strength which could impact variant classifications. Here, we provide guidance for combining such multiplexed functional data, incorporating a stepwise process from data curation and collection to model generation and validation. We illustrate the potential of this approach by showing the integration of multiplexed functional data from four MAVEs for the gene By following these steps, researchers can maximize the value of MAVEs, strengthen the functional evidence for clinical variant classification, reclassify more VUS, and potentially uncover novel mechanisms of pathogenicity for clinically relevant genes.

摘要

近年来,随着ClinVar中报告的意义未明变异(VUS)数量激增,大规模解决VUS变得势在必行。变异效应多重分析(MAVEs)能够在单个实验中测定数百到数千个基因变异的功能后果,正成为可用于临床基因变异分类的证据来源。越来越多的针对同一基因的MAVEs研究被发表,有时这些研究测量的是变异影响的不同方面。在需要考虑多种功能后果以更全面了解给定基因的变异效应时,整合来自多个MAVEs的数据可能会增加证据强度,从而影响变异分类。在此,我们提供整合此类多重功能数据的指导,包括从数据整理与收集到模型生成及验证的逐步过程。我们通过展示整合来自四个针对该基因的MAVEs的多重功能数据,来说明这种方法的潜力。通过遵循这些步骤,研究人员可以最大化MAVEs的价值,加强临床变异分类的功能证据,重新分类更多的VUS,并有可能揭示临床相关基因的新致病机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7631/11975307/ee85695e429a/nihpp-2503.18810v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7631/11975307/9403ba2b31a8/nihpp-2503.18810v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7631/11975307/f80b2920b491/nihpp-2503.18810v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7631/11975307/ee85695e429a/nihpp-2503.18810v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7631/11975307/9403ba2b31a8/nihpp-2503.18810v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7631/11975307/f80b2920b491/nihpp-2503.18810v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7631/11975307/ee85695e429a/nihpp-2503.18810v1-f0003.jpg

相似文献

[1]
Combining multiplexed functional data to improve variant classification.

ArXiv. 2025-3-24

[2]
Multimodal framework to resolve variants of uncertain significance in .

bioRxiv. 2024-6-8

[3]
Using multiplexed functional data to reduce variant classification inequities in underrepresented populations.

Genome Med. 2024-12-3

[4]
Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN.

Am J Hum Genet. 2021-12-2

[5]
Assigning credit where it's due: An information content score to capture the clinical value of Multiplexed Assays of Variant Effect.

bioRxiv. 2023-10-20

[6]
Assigning credit where it is due: an information content score to capture the clinical value of multiplexed assays of variant effect.

BMC Bioinformatics. 2024-9-6

[7]
Defining and Reducing Variant Classification Disparities.

medRxiv. 2024-4-12

[8]
Systematic large-scale application of ClinGen InSiGHT -specific ACMG/AMP variant classification criteria substantially alleviates the burden of variants of uncertain significance in ClinVar and LOVD databases.

medRxiv. 2024-5-4

[9]
Multi-objective prioritization of genes for high-throughput functional assays towards improved clinical variant classification.

Pac Symp Biocomput. 2023

[10]
Curation of OCA2 Variants of Uncertain Significance From Chinese Oculocutaneous Albinism Patients Based on Multiplex Assays.

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本文引用的文献

[1]
Multiplex and multimodal mapping of variant effects in secreted proteins via MultiSTEP.

Nat Struct Mol Biol. 2025-6-13

[2]
Functional evaluation and clinical classification of BRCA2 variants.

Nature. 2025-2

[3]
Saturation genome editing-based clinical classification of BRCA2 variants.

Nature. 2025-2

[4]
Site-saturation mutagenesis of 500 human protein domains.

Nature. 2025-1

[5]
Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations.

Nat Genet. 2025-1

[6]
A missense variant effect map for the human tumor-suppressor protein CHK2.

Am J Hum Genet. 2024-12-5

[7]
Using multiplexed functional data to reduce variant classification inequities in underrepresented populations.

Genome Med. 2024-12-3

[8]
High-resolution functional mapping of RAD51C by saturation genome editing.

Cell. 2024-10-3

[9]
Comprehensive analysis of the functional impact of single nucleotide variants of human CHEK2.

PLoS Genet. 2024-8

[10]
Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

Am J Hum Genet. 2024-9-5

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