A Comprehensive Report of Intrinsically Disordered Regions in Inherited Retinal Diseases

Abstract

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.

Methods: 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.

Main outcome measures: The main outcome measures were percent disorder, percent pathogenicity, number of total missense variants, and percent total missense variation.

Results: 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 p = 0.0240).

Conclusions: 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.

Keywords: IDR; IRD; RetNet; genetics; inherited eye diseases; intrinsically disordered regions; proteins.

Figure 1

Distribution of percentile of intrinsically disordered regions (IDRs) in all proteins showing highest distribution in 0,10 decile and lowest in 90,100 decile.

Figure 2

% disorder versus total number of missense variants. % disorder = (number of amino acids in IDRs/total number of amino acids in protein) × 100. Total number of missense variants is obtained from gnomAD browser.

Figure 3

% disorder versus % total missense. % disorder = (number of amino acids in IDRs/total number of amino acids in protein) × 100. % missense = (number of total missense variants/total number of amino acids in protein) × 100. Total number of missense variants is obtained from gnomAD browser.

Figure 4

% disorder versus # of total missense variants in 0–10% disorder decile. (a) % disorder versus # total missense variants in 0–10% disorder decile. (b) % disorder versus % total missense in 0–10% disorder decile. (c) % disorder versus # of total missense variants in 90–100% disorder decile. (d) % disorder versus % total missense in 90–100% disorder decile. % missense = (number of total missense variants/total number of amino acids in protein) × 100. % disorder versus total number of missense variants. % disorder = (number of amino acids in IDRs/total number of amino acids in protein) × 100.

Figure 5

% disorder versus % pathogenicity. % disorder = (number of amino acids in IDRs/total number of amino acids in protein) × 100. % pathogenicity = (number of pathogenic missense variants/total number of missense variants) × 100.

Figure 6

% disorder versus % pathogenicity in (a) 0–10% disorder decile and (b) 90–100% disorder decile. % disorder = (number of amino acids in IDRs/total number of amino acids in protein) × 100. % pathogenicity = (number of pathogenic missense variants/total number of missense variants) × 100.