Systemic Genotype-Phenotype Analysis of MYOC Variants Based on Exome Sequencing and Literature Review.
Li Xueqing, Xiao Xueshan, Li Shiqiang, Sun Wenmin, Wang Panfeng, Zhang Qingjiong
AI Summary
This study found rare MYOC missense variants, particularly in the olfactomedin domain, are strongly associated with primary open-angle glaucoma, guiding genetic testing and understanding disease mechanisms.
Abstract
Purpose
This study aims to characterize disease-causing variants in the myocilin gene (MYOC), which is associated with autosomal dominant primary open-angle glaucoma (adPOAG).
Design
Case-control study.
Methods
MYOC variants were collected from in-house exome sequencing data of 7092 individuals. Genotype-phenotype analysis and bioinformatics evaluation were used to distinguish potential pathogenic variants for POAG from others. MYOC mutations in published works of literature were also systemically analyzed.
Results
In total, 53 variants in MYOC were detected in the 7092 subjects, including 45 rare variants (MAF < 0.01) and 8 polymorphisms (MAF ≥ 0.01), or 48 missense variants and 5 truncation variants. There was no difference in the frequency of the 8 polymorphisms between subjects with and without POAG (P > 0.05). The total number of rare MYOC variants was significantly higher in POAG than that in in-house controls (P = 3.31E-14). The pathogenic/likely pathogenic variants (p.P254T, p.S341P, p.G367R, p.P370L, p.D378G, p.C433Y, and p.L486F) were exclusively present in 8 POAG but absent in in-house controls (P = 2.79E-10). Rare truncation MYOC variants were not enriched in POAG as compared with those in in-house controls (P = 0.28). Further analysis of previously reported MYOC variants suggested that pathogenic/likely pathogenic variants were enriched in the conserved olfactomedin domain. Truncation MYOC variants were scattered in the coding region, where only p.Q368∗ had relatively strong evidence to be causative for adPOAG, whereas most others are questionable.
Conclusions
Most MYOC variants contributing to adPOAG could be characterized as rare missense variants located in OLF-domain and predicted to be damaging through multiple tools. The effect of other variants, especially for truncation variants (except for p.Q368∗) need further clarification.
MeSH Terms
Shields Classification
Key Concepts5
The total number of rare MYOC variants (minor allele frequency < 0.01) was significantly higher in patients with primary open-angle glaucoma (POAG) than in in-house controls (P = 3.31E-14).
Pathogenic/likely pathogenic MYOC variants (p.P254T, p.S341P, p.G367R, p.P370L, p.D378G, p.C433Y, and p.L486F) were exclusively present in 8 patients with primary open-angle glaucoma (POAG) but absent in in-house controls (P = 2.79E-10).
Rare truncation MYOC variants were not enriched in patients with primary open-angle glaucoma (POAG) as compared with those in in-house controls (P = 0.28).
Most MYOC variants contributing to autosomal dominant primary open-angle glaucoma (adPOAG) could be characterized as rare missense variants located in the olfactomedin (OLF)-domain and predicted to be damaging through multiple tools.
The MYOC truncation variant p.Q368* had relatively strong evidence to be causative for autosomal dominant primary open-angle glaucoma (adPOAG), whereas most other truncation variants are questionable.
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