title: 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.
authors.affiliation: The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Li
authors.forename: Dingding
authors.initials: D
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Yuanfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Fang
authors.initials: F
authors.lastname: Lu
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
authors.forename: Fei
authors.initials: F
authors.lastname: He
authors.forename: Bo
authors.initials: B
authors.lastname: Gong
authors.forename: Li
authors.initials: L
authors.lastname: Cai
authors.forename: Ruiqiang
authors.initials: R
authors.lastname: Li
authors.forename: Shihuang
authors.initials: S
authors.lastname: Liao
authors.forename: Shi
authors.initials: S
authors.lastname: Ma
authors.forename: He
authors.initials: H
authors.lastname: Lin
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.forename: Hancheng
authors.initials: H
authors.lastname: Zheng
authors.forename: Ying
authors.initials: Y
authors.lastname: Shan
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Jianbin
authors.initials: J
authors.lastname: Hu
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.forename: Peiquan
authors.initials: P
authors.lastname: Zhao
authors.forename: Yiye
authors.initials: Y
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.forename: Yingchuan
authors.initials: Y
authors.lastname: Fan
authors.forename: Huanming
authors.initials: H
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009216:Myopia / Q000235:genetics*; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C099572:ZNF664 protein, human