蛋白质错误折叠作为遗传性耳聋机制的患病率研究

文献信息

中文摘要

背景： 听力损失是最常见的感觉缺陷，影响全球约5%的人口。耳聋变异数据库（DVD）是一个公开的耳聋变异资源，包含224个基因中的381,924个错义变异，其中303,577个被归类为意义不明的变异（VUS）。方法：为了应对评估每个耳聋相关VUS的挑战，我们评估了一系列概率框架，以基于ACMG/AMP建议量化计算证据的强度。首先，使用贝叶斯模型比较CADD和REVEL，模型参数分别来自ClinVar 2019数据集或标记的DVD变异。使用DVD数据集构建的REVEL模型显示出最佳的准确性、灵敏度和特异性。根据将每个基因分为三个区间（耐受、平均、不耐受）来纳入对错义变异的（不）耐受性，结果显示不耐受的DVD基因与更高的致病性先验概率（25.7%）一致，高于平均（10.7%）或耐受（8.7%）基因。最后，将蛋白质折叠稳定性的影响纳入贝叶斯模型，超越了更简单的版本，同时为疾病机制提供了生物物理原理。基于蛋白质折叠信息的贝叶斯模型，28,866个VUS达到致病性后验概率超过98%，被优先列为可能致病。结果：总体而言，54,752个错义变异（占381,924的14.3%）被预测会导致大于1.0 kcal/mol的适度蛋白质折叠去稳定，其中18,706个是优先VUS（占54,752的34%）。22,237个错义变异（占381,924的6.2%）被预测会导致至少2 kcal/mol的更严重蛋白质折叠去稳定，其中12,424个是优先VUS（占22,237的55.8%）。从这些VUS中，我们识别出12个先证者，其患者的遗传诊断升级为可能致病/致病。结论：我们重点介绍了两个导致明显结构破坏的变异，展示了生物物理表征对变异评估的影响。

英文摘要

Hearing loss is the most common sensory deficit impacting ~5% of the world's population. The Deafness Variation Database (DVD) is a public resource of deafness variants, containing 381,924 missense variants across 224 genes, with 303,577 classified as a variant of uncertain significance (VUS). To address the challenge of evaluating each deafness associated VUS, we evaluate a family of probabilistic frameworks to quantify the strength of computational evidence based on ACMG/AMP recommendations. First, CADD and REVEL are compared using Bayesian models parameterized using either a ClinVar 2019 dataset or labeled DVD variants. The REVEL model built using the DVD dataset demonstrates the best accuracy, sensitivity, and specificity. Incorporation of (in)tolerance to missense variation based on sorting each gene into three bins (tolerant, average, intolerant) shows that intolerant DVD genes are consistent with a higher prior probability of being pathogenic (25.7%) than average (10.7%) or tolerant (8.7%) genes. Finally, the impact of protein folding stability was incorporated into the Bayesian model and surpassed the simpler versions while also offering a biophysical rationale for the disease mechanism. The 28,866 VUSs that reach a posterior probability of pathogenicity above 98% based on the protein-folding informed Bayesian model were prioritized as likely to be pathogenic. Overall, 54,752 missense variants (14.3% of 381,924) are predicted to cause modest protein folding destabilization of greater than 1.0 kcal/mol, while 18,706 of these are prioritized VUSs (34% of 54,752). 22,237 missense variants (6.2% of 381,924) are predicted to cause more severe protein folding destabilization of at least 2 kcal/mol with 12,424 being prioritized VUSs (55.8% of 22,237). From these VUSs, we identify twelve probands where the patient's genetic diagnosis is upgraded to likely pathogenic/pathogenic. We highlight two variants that cause clear structural disruption, demonstrating the impact of biophysical characterization on variant evaluation.