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Bethany A. Kloss, Stuart W. J. Tompson, Kristina Whisenhunt, Samuel J. Huang, Thomas Rosenberg, Terri L Young; Whole Exome Sequencing Identifies a Rare Variant Co-segregating with High Myopia. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3606.
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© ARVO (1962-2015); The Authors (2016-present)
Myopic refractive error is the most common eye disorder worldwide. The severe form, high-grade myopia, is defined as having ≤ -6.00 diopters spherical equivalent. We sought to identify the causal gene mutation in a large, autosomal dominant high-grade myopia family using exome sequencing.
DNA was obtained from a multi-generational Danish family with 3 members affected by high-grade myopia ranging from -6.00 to -11.50 diopters. Whole exome sequencing was performed using the Roche Nimblegen SeqCap EZ Exome capture kit v3 and 2 x 100bp (paired-end) reads on an Illumina HiSeq2000 platform. Sequences were aligned to the GRCh37/hg19 human genome assembly using BWA and variants called using GATK. Single nucleotide polymorphisms (SNPs) and insertion/deletion changes were filtered and analyzed using the SNP and Variation Suite software v8.3 (Golden Helix).
Heterozygosity for a rare missense variant, c.97A>G (p.Ile33Val), in the retinol dehydrogenase 5 (RDH5) gene was identified in 3 affected family members by exome sequencing. The variant was not identified in 168 in-house control exomes. Disease status co-segregation was confirmed by Sanger sequencing. RDH5 maps to chromosome 12q13.2; 2 large-scale genome-wide association studies previously identified a significant association between myopia/refractive error and 2 SNPs located within RDH5. According to an in-house microarray expression dataset, RDH5 is expressed in developing/adult sclera, choroid and retina. Alternate allele frequencies, obtained from the Exome Aggregation Consortium database, were present in 0.22% in the general population and the non-Finnish European population. The variant affects an isoleucine residue that is evolutionarily highly conserved. In silico functional prediction algorithms (FATHMM and Polyphen2) anticipate the change to be damaging.
A rare variant in the RDH5 gene co-segregated with an autosomal dominant form of high-grade myopia in a Danish family. The variant is predicted to be the causative mutation within this family. Further analysis of the functional consequences of this variant will need to be assessed using cellular and animal model systems.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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