Genetic and clinical landscape of -associated MYP26: the most common cause of Mendelian early-onset high myopia with a unique inheritance.

AIMS

To elucidate genetic background of early-onset high myopia (eoHM) and characteristics of -associated MYP26.

METHODS

Variants in 14 genes reported to contribute to eoHM, including , were selected from exome sequencing data set and classified into different categories following American College of Medical Genetics and Genomics guidelines based on in silico prediction, associated phenotypes, confirmation and cosegregation analysis. The available clinical data of individuals were summarised.

RESULTS

Pathogenic and likely pathogenic variants in three of 14 genes were identified in 52 of 928 families with eoHM, including 29 in , 22 in and 1 in . For , 24 pathogenic variants (16 truncation and 8 missense) were identified in 66 women and 12 men, in whom 64 women and 4 men had eoHM by X-linked female-limited inheritance. Refraction ranged from -5.00 to -28.75 diopter (-12.58±4.83). Mild-to-moderately reduced cone responses were recorded in 76.9% (10/13) of patients with electroretinogram recordings. Most patients (75.9%, 41/54) had mild myopic fundus changes (C0 to C1). Genotype-phenotype analysis suggested that the myopic retinopathy degree was correlated with age and the variant's nature. Peripheral retinal degeneration was observed in 38.5% (5/13) patients using wide-field examinations.

CONCLUSION

This study reveals as the most frequently implicated gene for Mendelian eoHM. Truncations and highly scored missense variants in are pathogenic. Myopia due to mutations is transmitted in X-linked female-limited inheritance, manifests with mild cone impairment and slowly progresses to pathologic myopia. Identification of the most common cause for Mendelian eoHM provides a valuable starting point into the molecular mechanism of myopia.