EP46 MAVE：消灭 VUS 的大杀器

本期主要内容

做医学遗传的朋友都知道 VUS 有多烦：一份报告里冒出一堆"意义未明"的变异，既不能定致病也不能定良性，等于没给诊断。这期我们聊的 MAVE（Multiplexed Assays of Variant Effect ），就是目前消灭 VUS 最猛的一件武器：它用一次实验，把一个基因所有可能的突变全做一遍功能测试，提前画好一张"变异效应图谱"，解读的时候直接查表就行。本期节目，我们介绍一下 MAVE是什么、怎么做讲起——从 2010 年前后那几篇奠基作，到 BRCA1、PTEN 这些经典案例，到最近两年爆火的 RNU4-2 。最后介绍两个落地工具：存原始数据的 MaveDB，和把功能分数翻译成 ACMG 临床证据的 ClinMAVE，怎么用在解读里。

关键词（中英文对照）

多重变异效应检测Multiplexed Assays of Variant Effect (MAVE)

深度突变扫描Deep Mutational Scanning (DMS)

饱和基因组编辑Saturation Genome Editing (SGE)

意义未明的变异Variant of Uncertain Significance (VUS)

变异效应图谱Variant Effect Map

致病几率（PS3 证据）Odds of Pathogenicity (OddsPath)

ACMG/AMP 变异解读标准ACMG/AMP guidelines

ReNU 综合征 / 神经发育障碍ReNU syndrome / NDD

参考文献

方法学奠基

1. Fowler DM, Araya CL, Fleishman SJ, Kellogg EH, Stephany JJ, Baker D, Fields S. High-resolution mapping of protein sequence-function relationships. Nature Methods. 2010;7(9):741–746. https://www.nature.com/articles/nmeth.1492

2. Ernst A, Gfeller D, Kan Z, Seshagiri S, Kim PM, Bader GD, Sidhu SS. Coevolution of PDZ domain–ligand interactions analyzed by high-throughput phage display and deep sequencing. Molecular BioSystems. 2010;6(10):1782–1790. https://doi.org/10.1039/c0mb00061b

3. Hietpas RT, Jensen JD, Bolon DNA. Experimental illumination of a fitness landscape. PNAS. 2011;108(19):7896–7901. https://www.pnas.org/doi/full/10.1073/pnas.1016024108

4. Fowler DM, Fields S. Deep mutational scanning: a new style of protein science. Nature Methods. 2014;11(8):801–807. https://www.nature.com/articles/nmeth.3027

MAVE 命名与临床转向

1. Starita LM, Ahituv N, Dunham MJ, Kitzman JO, Roth FP, Seelig G, Shendure J, Fowler DM. Variant Interpretation: Functional Assays to the Rescue. American Journal of Human Genetics. 2017;101(3):315–325. https://doi.org/10.1016/j.ajhg.2017.07.014

经典临床基因案例

1. Findlay GM, Daza RM, Martin B, Zhang MD, Leith AP, Gasperini M, Janizek JD, Huang X, Starita LM, Shendure J. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018;562(7726):217–222. https://www.nature.com/articles/s41586-018-0461-z

2. Starita LM, Islam MM, Banerjee T, Adamovich AI, Gullingsrud J, Fields S, Shendure J, Parvin JD. A Multiplex Homology-Directed DNA Repair Assay Reveals the Impact of More Than 1,000 BRCA1 Missense Substitution Variants on Protein Function. American Journal of Human Genetics. 2018;103(4):498–508. https://doi.org/10.1016/j.ajhg.2018.07.016

3. Mighell TL, Evans-Dutson S, O'Roak BJ. A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships. American Journal of Human Genetics. 2018;102(5):943–955. https://doi.org/10.1016/j.ajhg.2018.03.018

非编码 RNA 的里程碑：RNU4-2

1. RNU4-2 ReNU 综合征首次报道（de novo 变异致病）。Nature. 2024.（建议正式引用时核对作者与卷期） https://www.nature.com/articles/s41586-024-07773-7

2. Saturation genome editing of RNU4-2 reveals distinct dominant and recessive neurodevelopmental disorders. 预印本 medRxiv. 2025. https://www.medrxiv.org/content/10.1101/2025.04.08.25325442v1 正式版：Nature. 2026. https://www.nature.com/articles/s41586-026-10334-9

数据库

1. Esposito D, Weile J, Shendure J, Starita LM, Papenfuss AT, Roth FP, Fowler DM, Rubin AF. MaveDB: an open-source platform to distribute and interpret data from multiplexed assays of variant effect. Genome Biology. 2019;20(1):223. https://genomebiology.biomedcentral.com/articles/10.1186/s13059-019-1845-6 数据库主页：https://www.mavedb.org

2. Rubin AF, et al. MaveDB 2024: a curated community database with over seven million variant effects from multiplexed functional assays. Genome Biology. 2025;26:13. https://link.springer.com/article/10.1186/s13059-025-03476-y

3. Ma C, Li Z, Tang X, Li P, Li L, Wang S, Wu J, Luo L, Liu Y, Zhang Z, Wang X. ClinMAVE: a curated database for clinical application of data from multiplexed assays of variant effect. Nucleic Acids Research. 2026;54(D1):D1355–D1363. https://academic.oup.com/nar/article/54/D1/D1355/8322704 数据库主页：https://ngdc.cncb.ac.cn/clinmave/

4. MaveMD: A functional data resource for genomic medicine. 预印本 medRxiv. 2025. https://www.medrxiv.org/content/10.1101/2025.11.14.25340130v1

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