Exome Sequencing Identifies ZNF644 Mutations in High Myopia

Abstract

Myopia is the most common ocular disorder worldwide, and high myopia in particular is one of the leading causes of blindness. Genetic factors play a critical role in the development of myopia, especially high myopia. Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders. Here we show a successful application of exome sequencing to identify a gene for an autosomal dominant disorder, and we have identified a gene potentially responsible for high myopia in a monogenic form. We captured exomes of two affected individuals from a Han Chinese family with high myopia and performed sequencing analysis by a second-generation sequencer with a mean coverage of 30× and sufficient depth to call variants at ∼97% of each targeted exome. The shared genetic variants of these two affected individuals in the family being studied were filtered against the 1000 Genomes Project and the dbSNP131 database. A mutation A672G in zinc finger protein 644 isoform 1 ( ZNF644) was identified as being related to the phenotype of this family. After we performed sequencing analysis of the exons in the ZNF644 gene in 300 sporadic cases of high myopia, we identified an additional five mutations (I587V, R680G, C699Y, 3′UTR+12 C>G, and 3′UTR+592 G>A) in 11 different patients. All these mutations were absent in 600 normal controls. The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE). Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, mutation may cause the axial elongation of eyeball found in high myopia patients. Our results suggest that ZNF644 might be a causal gene for high myopia in a monogenic form.

Author Summary

People with myopia see near objects more clearly than objects far away. Myopia is the most common ocular disorder worldwide, with a high prevalence in Asian (40%–70%) and Caucasian (20%–30%) populations. Although the etiologies of myopia have not yet been established, previous studies have indicated the involvement of genetic and environmental factors (such as close working habits, higher education levels, and higher socioeconomic class). Genetic factors play a critical role in the development of myopia, especially high myopia. In this study, we use exome sequencing, a powerful tool for a disease gene identification, to identify a gene involved in high myopia in a monogenic form among Han Chinese. Mutations in zinc finger protein 644 isoform 1 ( ZNF644) were identified as potentially responsible for the phenotype of high myopia. The main feature of high myopia is axial elongation of the eye globe. Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, a mutant ZNF644 protein may impact the normal eye development and therefore may underlie the axial elongation of the eye globe in high myopia patients. Further study of the biological function of ZNF644 will provide insight into the pathogenesis of myopia.