Department of Pediatric Ophthalmology and Strabismus, Wills Eye Hospital, Philadelphia, PA 19107, USA.
Retina Service, Wills Eye Hospital, Philadelphia, PA 19107, USA.
Genes (Basel). 2023 Aug 8;14(8):1601. doi: 10.3390/genes14081601.
BACKGROUND/PURPOSE: A comprehensive review of the degree of disorder in all genes in the Retinal Information Network (RetNet) Database is implicated in inherited retinal diseases (IRDs). Their association with a missense variation was evaluated.
IRD genes from RetNet were included in this study. Publicly available data on the genome aggregation database (gnomAD) were used to analyze the number of total and pathogenic missense variants. Metapredict, an accurate and high-performance predictor that reproduces consensus disorder scores, was used to calculate disorder.
The main outcome measures were percent disorder, percent pathogenicity, number of total missense variants, and percent total missense variation.
We included 287 RetNet genes with relevant data available from gnomAD. Mean percent disorder was 26.3% ± 26.0%, mean percent pathogenicity was 5.2% ± 11.0%, mean number of total missense variants was 424.4 ± 450.0, and mean percent total missense was 50.0% ± 13.4%. The percent disorder followed a bimodal distribution with the highest number of occurrences in the 0 to 10th disorder decile. The five outlier proteins in the first disorder decile with a higher-than-expected number of total missense variation were identified (HMCN1, ADGRV, USH2A, DYNC2H1, LAMA1, and SLC38A8). When excluded, % total missense was significantly associated with percent disorder (R = 0.238 and = 0.0240).
This novel study examining all genes implicated in IRDs found that the majority genes had a disorder in the 0 to 10th decile and were relatively intolerant to missense variation. This may have future utility when interpreting variants of undetermined significance and missense variants.
背景/目的：对视网膜信息网络（RetNet）数据库中所有基因紊乱程度的全面综述与遗传性视网膜疾病（IRDs）有关。评估它们与错义变异的关联。
本研究纳入了来自 RetNet 的 IRD 基因。利用基因组聚集数据库（gnomAD）中的公开数据，分析总致病性和致病性错义变异的数量。使用 Metapredict 计算混乱度，这是一种准确且高性能的预测器，可复制共识混乱评分。
主要观察指标为紊乱度百分比、致病性百分比、总错义变异数量和总错义变异百分比。
我们纳入了 287 个具有 gnomAD 相关数据的 RetNet 基因。平均紊乱度百分比为 26.3%±26.0%，平均致病性百分比为 5.2%±11.0%，总错义变异数量为 424.4±450.0，总错义变异百分比为 50.0%±13.4%。紊乱度呈双峰分布，第 0 至 10 个紊乱度十分位数中出现的频率最高。在第一个紊乱十分位中，有五个总错义变异数量异常高的外显子蛋白被鉴定出来（HMCN1、ADGRV、USH2A、DYNC2H1、LAMA1 和 SLC38A8）。当排除这些基因时，总错义变异百分比与紊乱度百分比显著相关（R=0.238，P=0.0240）。
这项研究对所有与 IRDs 相关的基因进行了分析，发现大多数基因在第 0 至 10 十分位存在紊乱，对错义变异相对不耐受。这在解释未确定意义的变异和错义变异时可能具有未来的应用价值。
