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Jessica Clare Gardner, Petra Liskova, Jonathan Ruddle, Bohdan Kousal, Michel Michaelides, Alison J Hardcastle; X-linked cone dystrophy and Blue Cone Monochromacy caused by novel and rare L/M opsin interchange haplotypes. . Invest. Ophthalmol. Vis. Sci. 2018;59(9):2325.
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© ARVO (1962-2015); The Authors (2016-present)
X-linked cone dystrophy/cone-rod dystrophy (XLCOD/CORD) and Blue Cone Monochromacy (BCM) are part of a spectrum of cone photoreceptor disorders caused by mutations of the long (L) and medium (M) wavelength cone opsin genes on Xq28. Symptoms include loss of colour vision and visual acuity, nystagmus, photophobia and reduced/absent cone ERG responses. A recently identified subset of mutations, present in exon 3 of OPN1LW and OPN1MW, known as interchange (IC) haplotypes, can cause either BCM or XLCOD/CORD. These IC haplotypes interfere with pre-mRNA splicing, causing exon 3 to be skipped. We have identified IC haplotypes in 4 more families enabling further characterisation of the IC mutation class.
Clinical evaluation of the 4 affected families included colour vision testing, measurements of VA, retinal imaging, electrophysiological assessment and adaptive optics scanning light ophthalmoscopy imaging (AOSLO). Genetic analysis incorporated exclusion of other causes of disease by combinations of next generation sequencing (NGS) panel testing of 211 disease genes, RPGR sequencing and Whole Exome Sequencing (WES). Sanger sequencing of coding exons, intron/exon boundaries and the locus control region of OPN1LW and OPN1MW was performed to identify IC haplotypes.
Four families with a diagnosis of COD/CORD/Cone dysfunction syndrome/BCM consistent with an X-linked pattern of inheritance were extensively investigated in order to find the causative mutations. Next generation sequencing excluded the majority of candidate genes but failed to adequately exclude the L/M opsin array. In 2 families, with an XLCOD/XLCORD phenotype, Sanger sequencing of the opsin array revealed a novel exon 3 haplotype, LIVVA, in both L and M genes that segregated with disease. In a further 2 families, diagnosed with BCM/XLCORD, an LVVVA haplotype in both L and M genes of the array was identified.
The 2 families with LIVVA had a progressive condition consistent with CORD, while the 2 families with LVVVA appeared to have a more variable phenotype. This report adds to the growing number of disease-causing opsin IC haplotypes. Further deep phenotyping, including AOSLO, will be required before phenotype genotype correlations can be made.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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