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Johannes Birtel, Philipp L. Mueller, Martin Gliem, Elisabeth Mangold, Frank G Holz, Christine Neuhaus, Hanno Joern Bolz, Peter Charbel Issa; Clinical evaluation of an intensively genotyped cohort of macular and cone/cone-rod dystrophy patients. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© 2017 Association for Research in Vision and Ophthalmology.
Macular and cone/cone-rod dystrophies are genetically and clinically heterogeneous retinal disorders. Although the phenotype of some diseases may be characteristic for a specific genotype, phenotype-genotype correlations have not been established in many cases. A comprehensive molecular diagnosis supports patient counseling and progression prediction. In this retrospective, observational study we clinically and genetically characterized a large cohort of macular and cone/cone-rod dystrophies.
A two-tier procedure was implemented to identify the molecular cause in 211 consecutive patients in a tertiary German referral center. If the retinal phenotype was highly suggestive for causative mutations in ABCA4, PRHP2 or BEST1, Sanger sequencing (and, in case of ABCA4, MLPA) for these genes was performed. If this initial molecular testing was negative or if the phenotype was not suggestive for retinopathy associated with these genes, targeted next-generation sequencing (NGS) on an Illumina Hiseq1500 system was carried out for 375 genes after enrichment using NimbleGen sequence capture technology. All patients underwent standardized clinical examination and imaging, including spectral domain optical coherence tomography, wide field fundus autofluorescence imaging and fundus photography. Retinal function testing included best corrected visual acuity, electroretinography and visual field testing.
Pathogenic mutations where identified in 166 (78%) out of the 211 patients. ABCA4, PRPH2 and BEST1 were responsible for 36%, 10% and 8% of the resolved cases. Mutations were distributed over 26 genes. Unexpected or rare phenotype-genotype correlations were identified in 8 cases (5%). Patients whose causative mutation remained unsolved frequently presented with phenotypes resembling central areolar choroidal dystrophy (CACD), mitochondrial retinal dystrophy, or unspecific adult vitelliform or pattern dystrophy.
Targeted NGS detected a large mutational spectrum in patients with macular and cone/cone-rod dystrophies, indicating the need for unbiased genetic testing for this genetically heterogeneous disease group. The phenotype characteristics shared by patients without detected mutations suggest common genetic causes that might explain subsets of this cohort.
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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