Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):4219-4224. doi: 10.1073/pnas.1615970114. Epub 2017 Apr 3.

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia.

Author information

1
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.
2
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325027, China.
3
The Eye Hospital of Wenzhou Medical University, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou 325027, China.
4
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
5
Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705.
6
Ningxia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, China.
7
Stowers Institute for Medical Research, Kansas City, MO 64110.

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, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant 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.

KEYWORDS:

BSG; de novo mutations; early-onset high myopia; rare inherited mutations

PMID:
28373534
PMCID:
PMC5402409
DOI:
10.1073/pnas.1615970114
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center