Exome sequencing on 20 probands with early-onset high myopia: identify variants in Retnet genes and interacting of genes in the candidate genes

Abstract

Purpose To expand our knowledge of the genetic basis of early-onset high myopia (eoHM), we performed a whole exome sequencing (WES) study to analyze the pathogenic gene variants in patients with eoHM. Methods 20 probands from unrelated families with the first sign of eoHM as well as their parents were enrolled in this study. All participants received comprehensive ophthalmic examinations. Variants were detected by WES. The candidate pathogenic variants were selected by multistep bioinformatics analyses. The protein-protein interaction (PPIs) network analysis with STRING and k mean clustering was applied for detecting the interacting of genes in the candidate genes and the ClusPro Server was used for protein-protein docking. Results Pathogenic variants were detected in 12 Retnet genes including EYS, ABCA4, USH2A, RP1, CYP4V2, BBS7, RHO, CRB1, CNGA1, RP2, CACNA1F, RPGR, all which were related to eoHM with retinitis pigmentosa (RP). Among them, the variants in X-linked genes accounted for 45%, including RPGR, RP2, and CACNA1F, of which variants in RPGR (30%) were the most common. Of 20 probands, 5 showed simple eoHM, 13 RP with eoHM and 2 syndromic RP with eoHM. The PPIs network analysis revealed that among the 12 candidate genes, 7 genes belong to the hub genes including EYS, ABCA4,USH2A, CRB1, CNGA1, CACNA1F, and RPGR. Among them, RPGR was the most important gene that connects 11 nodes in 13 nodes of STRING network with ARR3 gene, a well-known gene to be associated with eoHM, being included. The clustering analysis showed that 13 nodes belong to 3 clusters. Cluster I was G protein-coupled receptor signaling pathway interacting with cluster II enriched in microtubule organization and responsible for regulation of transport in primary retinal cilia. Protein-protein docking showed the protein encoded by ARR3 bind to the protein encoded by RPGR and Rho genes. Conclusion High myopia was considered as an earlier feature of RP patients from variations in some known genes responsible for RP accompanied by HM. PPIs network analysis revealed important modules of gene interacting and RPGR-ARR3-Rho complex was potentially related to high myopia development. Our study presented a new perspective on the pathological mechanism of eoHM and provided new insight and enlightenment for the future research on the molecular genetics of eoHM.