title: Trio-based exome sequencing arrests de novo mutations in early-onset high myopia.
abstract: The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to -6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in as-yet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, aBSGmutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generatedBsgmutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene,BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China; jinzb@mail.eye.ac.cn jqu@mail.eye.ac.cn lufan@mail.eye.ac.cn.
authors.forename: Zi-Bing
authors.identifier: 0000-0003-0515-698X
authors.initials: ZB
authors.lastname: Jin
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325027, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Wu
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Xiu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Chun-Yun
authors.initials: CY
authors.lastname: Feng
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Xue-Bi
authors.initials: XB
authors.lastname: Cai
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Jian-Yang
authors.initials: JY
authors.lastname: Mao
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Lue
authors.initials: L
authors.lastname: Xiang
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Kun-Chao
authors.initials: KC
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Xueshan
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Kloss
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325027, China.
authors.forename: Zhongshan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325027, China.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Shenghai
authors.initials: S
authors.lastname: Huang
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Meixiao
authors.initials: M
authors.lastname: Shen
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Cheng
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Xue-Wen
authors.initials: XW
authors.lastname: Cheng
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Zheng
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Ningxia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhuang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Qingjiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Terri L
authors.initials: TL
authors.lastname: Young
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110.
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China; jinzb@mail.eye.ac.cn jqu@mail.eye.ac.cn lufan@mail.eye.ac.cn.
authors.forename: Fan
authors.initials: F
authors.lastname: Lu
authors.affiliation: The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China; jinzb@mail.eye.ac.cn jqu@mail.eye.ac.cn lufan@mail.eye.ac.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
mesh_terms: D051926:Basigin / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D009216:Myopia / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: C497886:BSG protein, human; D051926:Basigin
keywords: BSG; de novo mutations; early-onset high myopia; rare inherited mutations