Whole-exome sequencing on 6215 school-aged children reveals the importance of genetic testing in high myopia

Abstract Importance High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. It is well-known that genetic factors play a significant role in the development of HM. Early school-aged population-based genetic screening and treatment should be performed to reduce HM complications. Objective To identify risk variants in a large HM cohort and to examine the implications of universal genetic testing of individuals with HM with respect to clinical decision-making. Design, setting, and participants In this cross-sectional study, we retrospectively reviewed whole-exome sequencing(WES) results for myopia-related genes in 6,215 school-aged students with HM who underwent germline genetic testing between September 2019 and July 2020. The study setting was a commercial genetic testing laboratory and a multicenter census of elementary and high schools from different educational systems. Participants were aged 6 to 20 years, including 355 primary school students, 1970 junior high school students, and 3890 senior high school students. Main outcomes and measures The frequency and distribution of positive germline variants and the percentage of individuals with HM (spherical equivalent refraction, SER ≤ -6.00D) in both eyes were detected using the whole-exome sequencing (WES) genetic testing approach. Results Among individuals with HM, molecular testing yielded 15.52% diagnoses based on systematic analysis of variants in 75 candidate myopic genes. We found 36 known variants in 490 (7.88%) HM cases and 235 protein-truncating variants (PTVs) in 506 (8.14%) HM cases. We found that diagnostic yield was significantly positively associated with SER ( P = 0.0108), which ranged from 7.66% in the common High Myopia group (HM, -8.00D ≤ SER ≤ -6.00D) to 11.90% in Extreme Myopia group (EM, SER < -10.00D). We also found that primary school students (≤ 11 years) with EM had the highest diagnostic rate of PTV variants (22.86%), which was 1.77 and 4.78 times that of the Ultra Myopia (UM, -10.00D ≤ SER < -8.00D) and HM, respectively. Conclusions and relevance Using whole-exome sequencing, multiple previously discovered mutations and PTVs which have not been reported to be associated with HM were identified in a substantial number of school-age students with HM. The high mutation frequency in younger students with EM can provide clues for genetic screening and further specific clinical examinations of HM to promote long-term follow-up assessment. Key Points Question Is genetic testing necessary in the diagnosis of hereditary high myopia? Findings A total of 271 potential pathogenic mutations were identified in 964 of 6,215 (15.52%) students with high myopia (HM) through systematic analysis of variants in 75 candidate genes, including 36 known variants and 235 variants that have not been reported to be associated with HM. Subsequently, whole-exome sequencing on individuals with high myopia grouped by age and degree of refractive error revealed 4.78 times higher protein-truncating variants in primary school children with extreme myopia group (SER < -10.00D, 23.08%) compared with the common high myopia group (-8.00D ≤ SER ≤ -6.00D, 4.78%, P = 0.00045). The results suggest that early genetic testing and screening for pathogenic variants is beneficial for young school-aged children with extreme myopia (SER < -10D). Meaning This study investigated the significance of whole-exome sequencing in the diagnosis of high myopia population. It revealed the genetic cause of high myopia, and is expected to guide future research and clinical diagnosis of high myopia. As part of the treatment and prevention of high myopia, genetic testing can detect the severity of myopia in young children.