Determining Genetic Cause of Posterior Staphylomas in Eyes with Pathologic Myopia by Whole Exome Sequencing.

Purpose: To identify genetic variants in posterior staphylomas in eyes with pathologic myopia using whole exome sequencing and to determine possible molecular mechanisms contributing to the pathogenesis. Design: An observational, case-control study. Participants: Two hundred sixty-four unrelated Japanese patients with myopia (≤ -0.50 diopters) and posterior staphyloma, which was diagnosed by ultra-widefield OCT, 3-dimensional magnetic resonance imaging, and Optos imaging. Methods: Whole exome sequencing was performed on genomic DNA from peripheral blood. After variant filtering, the allelic frequencies were compared with control data obtained from East Asian subsets of the 1000 Genomes Project Phase III, the Exome Aggregation Consortium, and the Japanese Multi-Omics Reference Panel using Fisher exact test. A gene panel was constructed based on 13 staphyloma-associated disorders. Variants showing significant frequency differences ( Main Outcome Measures: The statistically associated variants and genes, gene set enrichment analysis results, protein-protein interaction networks, and involvement of basement membrane structures, including the inner limiting membrane (ILM) and Bruch membrane, were studied. Results: Whole exome sequencing identified 16 656 missense variants in 8628 genes. Comparative allele frequency analyses with public databases revealed 3925 variants that had significantly higher allelic frequencies in the subjects. Of these, 81 genes overlapped with a curated staphyloma-related gene panel and were subjected to gene set enrichment analysis. The findings showed enrichment in basement membrane, extracellular matrix, and collagen-related pathways. The Conclusions: Variants in the Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.