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Cerys J Evans, Alice E Davidson, Nicole Carnt, Neyme Veli, Stephen J Tuft, Alison J Hardcastle; The mutational spectrum of anterior corneal dystrophies in the UK. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4824. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Corneal dystrophies are bilateral, inherited disorders that cause corneal opacity and result in visual impairment. The majority of dystrophies that affect the anterior cornea are caused by mutations in TGFBI. We sought to identify the spectrum of mutations causing anterior corneal dystrophies in a large UK cohort of mixed ethnicity.
Individuals clinically diagnosed with an epithelial, sub-epithelial, or stromal corneal dystrophy were recruited at Moorfields Eye Hospital, London. Each proband was clinically examined and provided a blood sample for DNA extraction. Depending on the phenotype, we screened the corneal dystrophy genes TGFBI, UBIAD1 or CHST6 by direct sequencing. Mutations upstream of CHST6, previously identified to be disease causing, were screened using a PCR based assay. If the proband was mutation negative, GSN sequencing and/or plasma electrophoresis was performed. Segregation analysis was undertaken when familial samples were available.
In 68 of 72 probands we identified nine different, previously reported, TGFBI mutations causing Reis-Bücklers, Thiel-Behnke, lattice or granular corneal dystrophy. Of the four probands who were TGFBI-mutation negative; two were subsequently identified to have mutations in GSN, resulting in a diagnosis of Meretoja Syndrome, and two had paraproteinaemic keratopathy confirmed by plasma electrophoresis. Interestingly, two probands with epithelial basement membrane dystrophy (EBMD) were also found to carry a mutation in TGFBI. There were 20 probands with macular corneal dystrophy; the majority had different homozygous or compound heterozygous mutations in CHST6, although p.(Leu200Arg) was found in multiple probands. Three previously reported mutations were identified in four probands with Schnyder corneal dystrophy.
In this large multi-ethnic cohort a limited spectrum of only nine mutations was responsible for all TGFBI-associated disease. Genotype-phenotype correlation was observed for all TGFBI mutations except p.(Gly623Asp), which was associated with a broad phenotypic spectrum; including clinical features of lattice corneal dystrophy, Reis-Bücklers dystrophy or EBMD. We have expanded the mutational spectrum of CHST6 with the identification of five novel mutations.
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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