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Wesley A Goar, Charles C Searby, S Scott Whitmore, Adam P DeLuca, Ahed Imtirat, Edwin M Stone, Ruti Pavari, Todd E Scheetz, Val Sheffield; Examination of sequencing data in three Israeli families with Keratoconus. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4823. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Keratoconus (KT) is the most common corneal dystrophy with an occurrence rate of 1 in every 2,000 people. KT causes the cornea to thin with age, becoming conical and leading to myopia, irregular astigmatism and corneal scarring. The age of onset is generally the teenage years with stabilization in the third and fourth decades of life. Incidence of KT does not seem to be more prevalent in a specific ethnic group or gender. Currently, corneal transplantation is the only treatment for KT when visual acuity is no longer correctable by contact lenses. We hypothesize that KT is a genetically heterogeneous disease that is caused by mutations in one of several genes.
Samples were obtained from 3 Israeli KT families (16 samples) and genotyped using an Affymetrix Genome-Wide SNP 6.0 microarray. The SNP data was analyzed for regions consistent with segregation within each of the families using MERLIN. Three samples with KT (one from each family) were chosen, sequenced using the Illumina HiSeq 2500 platform and analyzed using our exome pipeline. Resulting variants were filtered based upon variant quality, predicted function, and population prevalence (1000 genomes, ExAC). Spurious variants (based upon our local set of 1000+ exomes) and those in regions inconsistent with segregation were removed to create the final variant list, which was annotated with corneal expression (http://genome.uiowa.edu/otdb) to assist in prioritizing candidates.
No plausible variations were found in these three families in genes previously reported to cause KT. In addition, no single gene with plausible exonic disease-causing variations was shared across all three families. However, a few genes were found that are shared between two of the families and need further follow up. Figure 1 summarizes the family structure and numbers of plausible variations throughout the pipeline.
Our data supports the genetic heterogeneity of KT even within isolated populations. Further work is needed to identify the causative mutations in these families. Due to the isolated population we will continue to pursue these through ascertainment of additional families and family members. This will allow us to narrow the intervals of the genome in which the causative mutations are found.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
Figure 1. For each family, the individuals available for study, and the variant-level results at multiple stages of filtering are shown.
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