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Andrea L. Vincent, Joseph Carroll, Gerald A. Fishman, Dianne Sharp, Phyllis Summerfelt, Vesper Williams, Alfredo Dubra, Adam M. Dubis, Fulton Wong; Retinal Structure and Function in a Pedigree Cosegregating Achromatopsia and a Rhodopsin Mutation. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4591.
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© ARVO (1962-2015); The Authors (2016-present)
To characterize retinal structure and function in a family cosegregating CNGA3 and RHO F45L mutations, using electrophysiology and adaptive optics imaging. Recessive CNGA3 mutations manifest as achromatopsia (ACHM) that disrupts cone function, while a dominant rhodopsin mutation could potentially cause rod and cone dysfunction.
In one pedigree we identified two affected siblings with achromatopsia, with compound heterozygous mutations in CNGA3 detected on exome sequencing, which also detected a RHO F45L mutation. Cascade screening identified two adults with heterozygous CNGA3 L527R and RHO F45L mutations, one additional sibling with CNGA3 R227Cand RHO F45L and one adult with RHO F45L in isolation. RHO F45L is reported as a pathogenic cause of autosomal dominant retinitis pigmentosa in a number of families.(Berson et al. IOVS 2002;43:3027, Sung et al. PNAS 1991;88:6481). Comprehensive clinical examination included visual acuity, dilated fundus examination, electrophysiology (ERG), spectral domain optical coherence tomography (OCT), and adaptive optics scanning laser ophthalmoscopy (AO).
Two affected children presented with nystagmus, photophobia, and poor vision (20/200-20/100). ERG showed normal scotopic function but nondetectable photopic function consistent with congenital ACHM. Retinal imaging was limited by nystagmus but AO images of the photoreceptor mosaic revealed reduced cone structure and an intact rod mosaic. Few wave-guiding cones were observed consistent with previous findings in ACHM. (Genead et al. IOVS 2011;52:7298) One child with CNGA3 R227Cand RHO F45L, and two adult carriers of CNGA3 L527R and RHO F45L had normal vision, fundus, ERG and OCT. AO images of the photoreceptor mosaic revealed complete cone and rod mosaics, with density of cones and rods within a normal range in all three. Examination of the isolated RHO F45L carrier was similarly normal but AO imaging was not undertaken.
Comprehensive clinical characterization in this pedigree suggests that RHO F45L is not pathogenic within this pedigree and in the context of a CNGA3 mutation background. The ability to characterize older family members with ERG, SD-OCT and AO provides considerable reassurance in this family that the young achromats would unlikely develop future rod dysfunction as a result of their RHO F45L mutation.
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