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Johannes Birtel, Martin Gliem, Philipp Mueller, Frank G Holz, Christine Neuhaus, Hanno Joern Bolz, Peter Charbel Issa; Gene panel diagnosis for retinitis pigmentosa - phenotypic characteristics of unresolved cases. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3815.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis pigmentosa (RP) is a genetically and clinically heterogeneous disease. Numerous RP genes have been described, but in a considerable number of cases, no disease-causing mutations are detected in these genes. Potential reasons are deep intronic mutations, changes in regulatory regions, mutations in as yet unknown genes, or phenocopies of RP. To detect potential clinical differences between mutation-positive and -negative patients, we investigated the phenotype and associated diseases in a retrospective, observational clinical study.
To determine the underlying molecular changes in RP patients, targeted next-generation sequencing on an Illumina Hiseq1500 system was carried out for 60 arRP and 23 adRP genes after enrichment using NimbleGen sequence capture technology. Thirty six patients were analyzed in a tertiary referral center in Germany based on clinical and demographical aspects. All patients underwent standardized clinical examination and imaging, including spectral domain optical coherence tomography, wide field fundus autofluorescence imaging and fundus photography. To assess retinal function, best corrected visual acuity, electroretinography and visual field testing were performed.<br />
Pathogenic mutations where identified in 25 (69%) out of 36 patients. Of the 11 patients without detected disease-causing mutation, only one had an affected family member and none had confirmed parental consanguinity, 6 showed no bone spicule pigmentation (RP sine pigmento) and 5 had an additional systemic autoimmune disease, such as hashimoto's thyroiditis or rheumatoide polyarthritis. None of these two clinical findings applied to any patient in the group defined by a specific genetic defect. Age of disease onset (first symptoms) was above 40 years in 7 out of 11 (64%) patients without and 4 out of 25 (16%) with a mutation in a known RP gene.
Phenotypic and demographic difference between RP patients might be used as a tool to stratify patients with and without detectable disease-causing mutations. The high rate of autoimmune diseases in patients without molecular genetic confirmation for a hereditary retinal disease points to a multifactorial disease process in a subgroup of RP patients.
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