Unraveling Pathogenic Variants and the Protein Interaction Landscape in 20 Families with Early-onset high myopia

Purpose To expand our current understanding of the genetic basis of eoHM, we carried out a whole exome sequencing (WES) study to identify potential causal variations in patients with eoHM. Methods Twenty probands with the first sign of eoHM were enrolled in this study and Phenotype were analyzed on the basis of clinical examinations.The pathogenic variants were identified using WES.Variants in candidate genes were analyzed by multistep bioinformatics analyses and the pathogenicity of the identified variant was evaluated subject to ACMG guidelines. The protein-protein interactions (PPIs) network analysis were employed to examine the interaction of candidate gene-related proteins. Results Pathogenic variants were detected in 12 Retnet genes. X-linked genes (RPGR, RP2, and CACNA1F) accounted for 45% (9/20) of the cases, of which variants in RPGR gene were found in approximately one-third (6/20) of the probands with eoHM. The phenotype analysis presented that 5 probands had simple eoHM and 13 probands had retinitis pigmentosia (RP) accompanied by eoHM as well as 2 syndromic RP with eoHM. PPIs network analysis found that RPGR was the most important gene of STRING network with ARR3 gene, a well-known gene to be associated with eoHM. Protein-protein docking showed the protein encoded by ARR3 bind to the protein of RPGR and RHO genes.In this study, the pathogenic variants in 12 genes known to be responsible for retinal diseases were found in 20 probands with eoHM. The analysis on interacting of candidate genes by STRING revealed that RPGR-ARR3-Rho complex was potentially related to high myopia development. Conclusion Our study expanded the spectrum of candidate genes associated with eoHM, which provide clues for genetic screening and provided new insight and enlightenment for the future research on the molecular genetics of eoHM.