BackgroundPopulation‐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.MethodsAll 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.ResultsThe 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.ConclusionsA 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.

中文翻译：

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基因组聚集数据库第 4 版——等位基因频率变化和对肌张力障碍变异解释的影响


背景种群规模数据库主要有助于变异解释。与 v2.1.1 相比，最近发布的基因组聚合数据库 （gnomAD） v4 的样本量增加了 >5。v2.1.1 中没有的致病性变异现在以相当大的速度在 v4 中注册。对肌张力障碍变异解读的影响尚不清楚。方法所有与最常见的孤立性肌张力障碍显性形式相关的精选变异均从国际帕金森病和运动障碍协会基因数据库中提取。我们比较了 gnomAD v2.1.1 和 v4 之间的变异种群频率和基因限制指标。结果大多数导致肌张力障碍的变异 （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 个变体中，27 个 （12.3%） 在 v4.1 中首次出现，包括已确定的致病性等位基因。GNAL 和 KMT2B 的基因限制在 v4 中显著降低。结论在 gnomAD v4 中观察到越来越多的肌张力障碍相关等位基因。种群规模数据中的存在并不排除致病性。© 2024 作者。由 Wiley Periodicals LLC 代表国际帕金森和运动障碍协会出版的《运动障碍》。