ABSTRACT
Purpose: This observational study aimed to identify mutations in monogenic syndromic high myopia (msHM) using data from reported samples (n = 9370) of the Myopia Associated Genetics and Intervention Consortium (MAGIC) project. Methods: The targeted panel containing 298 msHM-related genes was constructed and screening of clinically actionable variants was performed based on whole exome sequencing. Capillary sequencing was used to verify the identified gene mutations in the probands and perform segregation analysis with their relatives. Results: A total of 381 candidate variants in 84 genes and 85 eye diseases were found to contribute to msHM in 3.6% (335/9370) of patients with HM. Among them, the 22 genes with the most variations accounted for 62.7% of the diagnostic cases. In the genotype-phenotype association analysis, 60% (201/335) of suspected msHM cases were recalled and 25 patients (12.4%) received a definitive genetic diagnosis. Pathogenic variants were distributed in 18 msHM-related diseases, mainly involving retinal dystrophy genes (e.g. TRPM1, CACNA1F, and FZD4), connective tissue disease genes (e.g. FBN1 and COL2A1), corneal or lens development genes (HSF4, GJA8, and MIP), and other genes (TEK). The msHM gene mutation types were allocated to four categories: nonsense mutations (36%), missense mutations (36%), frameshift mutations (20%), and splice site mutations (8%). Conclusions: This study highlights the importance of thorough molecular subtyping of msHM to provide appropriate genetic counselling and multispecialty care for children and adolescents with HM.