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Terri L. Young, Thomas P. Klemm, Steve Rozen, Erica Burner- Nading, Liang Goh, Felicia Hawthorne, Seang Mei Saw, Caldwell Powell, Vincent J. Soler, Khanh-Nhat Tran-Viet; Novel Gene identification for Autosomal Dominant High-grade Myopia using Whole Exome Sequencing. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2256.
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© ARVO (1962-2015); The Authors (2016-present)
To identify a gene for autosomal dominant high-grade myopia in a large Caucasian pedigree using deep sequencing technology.
A 15-member family with high-grade myopia (8 affected-with a mean affected spherical equivalent of -12.00D) was ascertained. Next-generation sequencing at 50X using the Illumina Hi Seq technology and whole exome capture processing was performed. Sequence reads were aligned, and processed for single nucleotide variant and insertion/deletion calls. In-house pipeline filtering analyses, along with comparisons using the 1000 Genomes and dbSNP databases, were performed. Reverse transcription expression studies of systemic and ocular tissues were performed with discovered gene exon-specific primers, using GAPDH as a housekeeping reference gene.
A novel premature stop codon mutation (Q53X) was discovered in the synthesis of cytochrome c oxidase subunit 2 gene (SCO2), which maps to chromosome 22q13.33. This mutation followed segregation in all affected family members, and was not found in 800 ethnically-matched control DNA samples. PCR sequencing of the SCO2 coding exon conducted in an additional 140 ≤ -6.00 D high-myopia cases implicated 2 known rare polymorphisms (rs74315511 and rs8139305) and 1 novel variant that were all heterozygous for the reference alleles. Rs74315511 (c.418G>A) and Rs8139305 (c.776C>T) are missense mutations predicted to cause E140K and A259V substitutions, respectively. The novel missense mutation (c.341G>A) causes a substitution of R114H. All variants were negative across a total of 2400 chromosomes, and in silico Polyphen2 software predicted the mutations to be deleterious. Fisher exact testing of the 4 functional variants relative to 1000 non-myopic controls suggests that all SCO2 variants are associated with high myopia (p = 2.48 x 10-4). Expression of SCO2 was determined in the retina, retinal pigment epithelium, and sclera of 24-week fetal and adult eye tissues.
SCO2 gene mutations were found to segregate with high-grade myopia in a large autosomal dominant pedigree and three additional ethnically-matched cases. The gene product is implicated in cellular copper homeostasis. Copper deficiency has historically been associated with myopic refractive error development. A biologic mechanism for this gene may involve poor collagen and elastin cross-linking of the scleral wall, and/or subtle retinal photoreceptor alteration. This is the first identification of a causative gene for autosomal dominant high-grade myopia in Caucasians.
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