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基因组参考和人口数据集对于在遗传性视网膜疾病中引起疾病的变异的注释和优先级的重要性

Stefan T Stafie^1,2, Mark Lindquist^1,2, Samuel Kusher-Lenhoff^1,2

¹Department of Ophthalmology, University of Washington, Seattle, Washington, USA.

Ophthalmic genetics

|August 13, 2025

概括

使用更新的人类基因组参考和多样化的人口数据库显著提高了鉴定遗传性视网膜疾病 (IRD) 中引起疾病的变异的准确性. 这提高了患者的分子诊断.

科学领域:

基因组学和生物信息学
眼科和遗传医学眼科和遗传医学

背景情况:

测序技术的进步增加了变体识别,需要对致病变体进行准确的功能影响评估.
在遗传视网膜疾病 (IRD) 基因中优先考虑变异需要强大的功能注释.
人类基因组参考组合和人口数据库的选择极大地影响了变体解释.

研究的目的:

证明使用精细的人类基因组参考组件和多样化的人口数据库用于IRD基因变异的功能注释的重要性.
为了比较不同基因组构建和IRD基因的人口数据库之间的变异注释指标.
为采用最新的基因组资源提供经验证据,以改善IRD中的变异优先级和分子诊断.

主要方法:

基因组聚合数据库 (gnomAD) 版本3.1.2 (v3) 和4.1.0 (v4) (与GRCh38保持一致) 的变异数据与版本2.1.1 (v2) (与GRCh37保持一致) 的变异数据进行了比较.
使用的变异效应预测 (VEP),联合注释依赖枯竭 (CADD) 评分,以及ClinVar致病性注释.
生成接收机操作特征 (ROC) 曲线,以计算曲线下的面积 (AUC) 和精度回忆曲线下的面积 (AUPRC),以获得变量预测的准确性.

主要成果:

最新的基因组构建 (GRCh38) 和人口数据库 (gnomAD v4) 在区分病原性和非病原性变体时,实现了0.99的AUC和0.98的AUPRC.
使用更新资源进行了改进的功能注释,大大提高了变种病原性预测的准确性.
更多样化的人口数据有助于识别罕见变异,并提供了对IRD变异病原性更深入的见解.

结论:

采用最新的基因组构建和人口数据库对于在IRD中准确的功能注释和引起疾病的变异优先级至关重要.
增强的变体注释指标提高了区分致病变体的能力,从而导致更完整的分子诊断.
这项研究为更新基因组资源提供经验支持,以推进遗传视网膜疾病的诊断和理解.

关键词:

这就是为什么CADD是CADD.遗传性视网膜疾病遗传性视网膜疾病病原性变异是一种病原性变异.人口数据库人口数据库.变种注释变种注释

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