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Baojian Fan, Kevin Linkroum, Dan Yi Wang, Elizabeth DelBono, John Borchert, Louis R Pasquale, Janey L. Wiggs; Whole exome sequencing suggests that mutations in known glaucoma genes do not contribute to pigmentary dispersion syndrome. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2130.
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© ARVO (1962-2015); The Authors (2016-present)
Pigment dispersion syndrome is an important cause of glaucoma in the young adult population. While many cases appear to be sporadic, families exhibiting autosomal dominant inheritance have been described suggesting a significant genetic contribution to disease. In this study we have completed whole exome sequencing (WES) for 9 families affected by pigment dispersion syndrome and glaucoma inherited as an autosomal dominant trait.
After obtaining informed consent DNA was prepared from blood samples of 44 individuals (9 families) affected by pigment dispersion syndrome and/or pigmentary glaucoma. Pigment dispersion syndrome cases had characteristic iris transillumination defects. Pigmentary glaucoma was defined as having evidence of optic nerve disease (cup-disc ratio >0.7, and/or visual field defects corresponding to the nerve fiber layer in at least one eye) and IOP >21 mmHg in addition to the iris transillumination defects. WES was performed using exon capture by the Agilent SureSelect Human All Exon v5+UTR+Mito kit (74.6 Mb target region), followed by sequencing on Illumina HiSeq 2000. The Ocular Genomics Institute WES pipeline was used to align sequence reads and complete variant calling and annotation. Average coverage of 105× was obtained for 99% of coding sequences.
Potentially disease causing variants in the genes known to cause early-onset glaucoma (CYP1B1, FOXC1, LTBP2, MYOC, OPTN, PAX6, PITX2, TBK1 and TEK) or contribute to primary open angle glaucoma (POAG) (ABCA1, AFAP1, ATXN2, CAV1, CDKN2B-AS1, FNDC3B, GAS7, GMDS, PMM2, SIX6, TGFBR3, TMCO1 and TXNRD2) were investigated in the WES data. While common coding sequence variants were identified in ABCA1, AFAP1, ATXN2, CYP1B1, FNDC3B, FOXC1, LTBP2, MYOC, OPTN, PMM2, SIX6, TBK1, TEK, TGFBR3 and TXNRD2, none of these fulfilled the criteria for disease causing alleles: rare in the general population (less than 1% in the Exome Aggregate Consortium dataset), segregation in all affected family members, and predicted to be pathogenic by SIFT and PolyPhen-2.
Using WES, coding sequence variants in the genes known to cause early-onset glaucoma or contribute to POAG were not identified in families affected by pigment dispersion syndrome or pigmentary glaucoma. These results suggest that a novel set of genes contribute to these important conditions.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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