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Wesley Goar, Carly van der Heide, Benjamin Roos, Wallace L M Alward, Young H Kwon, Michael Anderson, Val Sheffield, Todd E Scheetz, John H Fingert; EXOME-BASED INVESTIGATION OF THE GENETIC BASIS OF PIGMENT DISPERSION SYNDROME. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2836.
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© ARVO (1962-2015); The Authors (2016-present)
Pigment dispersion syndrome (PDS), release of pigment from the iris, may cause ocular hypertension and pigmentary glaucoma, a secondary open angle glaucoma. Multiple lines of evidence have suggested that PDS has a genetic basis, such as rare pedigrees with autosomal dominant inheritance of disease and animal models. However, no causative mutations have been identified in humans. The goal of this study is to test a cohort of PDS patients for rare disease-causing mutations within candidate genes that are known to cause pigment dispersion in mice.
Whole exome sequencing was performed on a cohort of PDS patients (n=362) and controls (n=210) using standard exome capture and sequencing methods. Analysis was performed using a tiered testing approach evaluating changes in mutational load across different sets of candidate genes. As a primary analysis, genes known to cause PDS in mice (TYRP1, GPNMB, LYST, DCT, and MITF) were evaluated for loss of function mutations. In a second analysis, we interrogated 21 additional candidate genes with established roles in melanogenesis for loss of function mutations. We also analyzed all non-synonymous or splice-altering variants within the entire exome were analyzed using logistic regression. Finally, we performed a gene-based SKAT-O analysis to test for evidence of increased mutation burden in PDS.
No statistically significant associations were identified in the primary analysis (loss of function mutations in TYRP1, GPNMB, LYST, DCT, and MITF). However, we detected four unique loss of function mutations within these genes associated with pigment dispersion in mice. Of these, three are nonsense mutations detected in the PDS cohort, one in each of three candidate genes (TYRP1, LYST, and DCT). Our SKAT-O analysis provided us with multiple statistically significant genes that are important to proper plasma membrane function.
No association was detected between loss of function mutations in top candidate genes (TYRP1, GPNMB, LYST, DCT, and MITF) and PDS. However, three rare loss of function mutations in TYRP1, LYST, and DCT were identified that are or unknown significance. These results suggest that larger studies will be necessary to provide statistical support for an association between candidate genes and PDS. Alternatively, functional studies may also be used to support pathogeneticitypathogenicity of these rare variants.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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