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Isabelle S. Audo, Kinga M. Bujakowska, Mélanie Letexier, Jean-Paul Saraiva, Saddek Mohand-Saïd, Botond Roska, Thierry Léveillard, Shomi S. Bhattacharya, José-Alain Sahel, Christina Zeitz; An Unusual Autosomal Dominant Retinal Dystrophy Combining Inner Retinal Dysfunction And Progressive Cone Dystrophy Is Associated With A Novel Gene Defect. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1226.
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To phenotypically and genetically characterize an autosomal dominant retinal dystrophy with inner retinal dysfunction and progressive cone dystrophy.
Detailed phenotypic characterization was performed on 9 affected family members spanning 2 generations including precise family history, best corrected visual acuity, slit lamp examination, kinetic and static perimetry, full field and multifocal ERG according to ISCEV standards, fundus autofluorescence imaging and spectral domain OCT. Known gene defects underlying autosomal dominant inner retinal dysfunction were studied with Sanger sequencing and targeted next generation sequencing (NGS). Subsequently, whole exome sequencing was applied on two affected and one unaffected family members.
Onset of symptoms in this family appears in the mid to late thirties with progressive bilateral decreased vision and photophobia. All affected members initially display an electronegative bright flash scotopic ERG response with subsequent decrease in photopic responses. Fundus autofluorescence imaging was normal at onset of symptoms before showing atypical autofluorescence changes in the macular region. These changes were associated with peculiar reflectance features within the foveal region followed by progressive thinning of the outer nuclear layer on spectral domain OCT. After exclusion of known gene defects underlying autosomal dominant inner retinal dysfunction and targeted NGS, whole exome sequencing identified variants in different novel candidate genes, of which only one co-segregated with the phenotype. Transcriptomic and proteomic databases were indicative for cone photoreceptor and inner retinal expression.
This family is presenting with an unusual autosomal dominant phenotype associating both an inner retinal dysfunction with progressive cone degeneration and structural retinal abnormalities never reported before. State-of-the-Art sequencing and database analysis suggest that this family is associated with a novel gene defect. Expression studies and functional assays will give further insight on the role of this gene in retinal pathophysiology.
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