Exome Sequence Analysis of 14 High-Grade Myopia Families

Abstract

Purpose : To identify causal gene mutations in a cohort of 14 families with autosomal dominant high-grade myopia using exome sequencing.

Methods : Genomic DNA from selected individuals in 14 large Caucasian families with high-grade myopia was obtained and analyzed through exome sequencing. Variants were filtered through a multi-step process, and potential pathogenic variants were confirmed by Sanger sequencing. Additional available affected and unaffected family members were screened for co-segregation of each variant with high-grade myopia when available. Candidate genes and chromosomal loci previously associated with myopic refractive error and its endophenotypes were also screened.

Results : A total of 102 rare/novel heterozygous variants in as many genes were identified in 10 out of 14 probands. Each variant was nonsynonymous and co-segregated with affection status. Of the 102 variants, none were identified in genes known to cause myopia or in genes closest to single nucleotide polymorphisms of refractive error genome-wide association studies (GWAS). Ten variants were identified within myopia-associated loci. Twenty-nine of the variants were novel changes. Variants were not identified in more than one family.

Conclusions : Ten variants within loci associated with myopia were found in seven families with high-grade myopia, two of which were novel. No novel/rare gene variants identified by published GWAS for refractive error or its endophenotypes were noted in our cohort. We identified an additional 92 variants, 29 of which were novel, as candidates for pathogenicity in high-grade myopia. These variants will require future study in additional patients with high-grade myopia, functional analysis, and/or animal modeling in order to determine their role in the phenotype. Nevertheless, variants that are novel or located within myopia-associated loci presented in this study provide new genes for consideration in the pathogenesis of high-grade myopia, and may aid in the development of genetic profiling of those at greatest risk for attendant ocular morbidities of this disorder.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.