The Genetic Confirmation and Clinical Characterization of LOXL3-Associated MYP28: A Common Type of Recessive Extreme High Myopia.

Purpose: In previous studies, biallelic LOXL3 variants have been shown to cause autosomal recessive Stickler syndrome in one Saudi Arabian family or autosomal recessive early-onset high myopia (eoHM, MYP28) in two Chinese families. The current study aims to elucidate the clinical and genetic features of LOXL3-associated MYP28 in seven new families and two previously published families.

Methods: LOXL3 variants were detected based on the exome sequencing data of 8389 unrelated probands with various ocular conditions. Biallelic variants were identified through multiple online bioinformatic tools, comparative analysis, and co-segregation analysis. The available clinical data were summarized.

Results: Biallelic LOXL3 variants were exclusively identified in nine of 1226 families with eoHM but in none of the 7163 families without eoHM (P = 2.97 × 10-8, Fisher's exact test), including seven new and two previously reported families. Seven pathogenic variants were detected, including one nonsense (c.1765C>T/p.Arg589*), three frameshift (c.39dupG/p.Leu14Alafs*21; c.544delC/p.Leu182Cysfs*3, c.594delG/p.Gln199Lysfs*35), and three missense (c.371G>A/p.Cys124Tyr; c.1051G>A/p.Gly351Arg; c.1669G>A/p.Glu557Lys) variants. Clinical data of nine patients from nine unrelated families revealed myopia at the first visit at about 5 years of age, showing slow progression with age. Visual acuity at the last visit ranged from 0.04 to 0.9 (median age at last visit = 5 years, range 3.5-15 years). High myopic fundus changes, observed in all nine patients, were classified as tessellated fundus (C1) in five patients and diffuse choroidal atrophy (C2) in four patients. Electroretinograms showed mildly reduced cone responses and normal rod responses. Except for high myopia, no other specific features were shared by these patients.

Conclusions: Biallelic LOXL3 variants exclusively presenting in nine unrelated patients with eoHM provide firm evidence implicating MYP28, with an estimated prevalence of 7.3 × 10-3 in eoHM and of about 7.3 × 10-5 in the general population for LOXL3-associated eoHM. So far, MYP28 represents a common type of autosomal recessive extreme eoHM, with a frequency comparable to LRPAP1-associated MYP23.