Systemic Genotype-Phenotype Analysis of MYOC Variants Based on Exome Sequencing and Literature Review.

Objective: This study aims to characterize disease-causing variants in the myocilin gene (MYOC), which is associated with autosomal dominant primary open-angle glaucoma (adPOAG).

Methods: 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.