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

Publications // Young Lab // Apr 18 2017

PubMed ID: 28373534

Author(s): Jin ZB, Wu J, Huang XF, Feng CY, Cai XB, Mao JY, Xiang L, Wu KC, Xiao X, Kloss BA, Li Z, Liu Z, Huang S, Shen M, Cheng FF, Cheng XW, Zheng ZL, Chen X, Zhuang W, Zhang Q, Young TL, Xie T, Lu F, Qu J. Trio-based exome sequencing arrests de novo mutations in early-onset high myopia. Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):4219-4224. doi: 10.1073/pnas.1615970114. Epub 2017 Apr 3. PMID 28373534

Journal: Proceedings Of The National Academy Of Sciences Of The United States Of America, Volume 114, Issue 16, 04 2017

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.