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

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.

• Authors: Xueqing Li, Xueshan Xiao, Shiqiang Li, Wenmin Sun, Panfeng Wang, Qingjiong Zhang
• Journal: Asia-Pacific journal of ophthalmology (Philadelphia, Pa.) (Asia Pac J Ophthalmol (Phila)) 2021 Mar-Apr 01 Vol. 10 Issue 2 Pg. 173-182 ISSN: 2162-0989 [Electronic] China
• PMID: 33793440 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2021 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.

Chemical References

• Cytoskeletal Proteins
• Eye Proteins
• Glycoproteins
• trabecular meshwork-induced glucocorticoid response protein

Topics

• Case-Control Studies
• Cytoskeletal Proteins (genetics)
• Exome
• Eye Proteins (genetics)
• Genotype
• Glaucoma, Open-Angle (genetics)
• Glycoproteins (genetics)
• Humans
• Mutation
• Phenotype