基因组聚合数据库第 4 版--肌张力障碍中的等位基因频率变化及其对变异解释的影响。

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY Movement Disorders Pub Date : 2024-11-21 DOI:10.1002/mds.30066

Elisabetta Indelicato, Anna Eberl, Sylvia Boesch, Lara M Lange, Christine Klein, Katja Lohmann, Michael Zech

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引用次数: 0

摘要

背景：群体规模的数据库对变异解释有重大贡献。最近发布的基因组聚合数据库（gnomAD）v4与v2.1.1相比，样本量增加了5倍以上。v2.1.1中没有的致病变异现在在v4中的登记率相当高。这对肌张力障碍变异解释的影响尚不清楚：方法：我们从国际帕金森病和运动障碍协会基因数据库中提取了所有与最常见的分离性肌张力障碍显性形式相关的策划变异。我们比较了 gnomAD v2.1.1 和 v4 的变异群体频率和基因约束指标：大多数肌张力障碍致病变异（192/247，77.7%）在较新的 gnomAD 版本中仍然不存在。在v2.1.1中缺失的219个变异中，有27个（12.3%）首次出现在v4.1中，其中包括已经确定的致病等位基因。在 v4.1 中，GNAL 和 KMT2B 的基因限制显著减少：gnomAD v4中出现了越来越多的肌张力障碍相关等位基因。© 2024 The Author(s).运动障碍》由 Wiley Periodicals LLC 代表国际帕金森和运动障碍协会出版。

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Genome Aggregation Database Version 4-Allele Frequency Changes and Impact on Variant Interpretation in Dystonia.

Background: Population-scale databases majorly contribute to variant interpretation. The recently released Genome Aggregation Database (gnomAD) v4 offers a >5-fold increased sample size compared to v2.1.1. Pathogenic variants absent from v2.1.1 are now registered in v4 at a considerable rate. The implications on variant interpretation in dystonia are unknown.

Methods: All curated variants linked to the most common dominant forms of isolated dystonia were extracted from the International Parkinson's Disease and Movement Disorder Society Gene database. We compared variant population-frequencies and gene constraint metrics between gnomAD v2.1.1 and v4.

Results: The majority of dystonia-causing variants (192/247, 77.7%) remained absent from the newer gnomAD version. Of 219 variants absent from v2.1.1, 27 (12.3%) appeared for the first time in v4.1, including well-established pathogenic alleles. Gene constraints for GNAL and KMT2B significantly decreased in v4.

Conclusions: A growing number of dystonia-linked alleles are seen in gnomAD v4. The presence in population-scale data does not preclude pathogenicity. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.