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Rando Allikmets, Yajing Xie, Winston Lee, Luz Amaro-Quireza, Tomasz Gambin, Shalini N Jhangiani, Bo Yuan, James R Lupski, Stephen H Tsang; RDH11, a new gene for autosomal recessive retinitis pigmentosa with syndromic features. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3266.
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To determine the causal gene and mutations in a family presenting with autosomal recessive retinitis pigmentosa (arRP) with syndromic features.
Detailed medical history and ophthalmic examination, including fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and ISCEV-standardized electroretinography, were performed on all family members, including 3 affected children and asymptomatic parents. All family members were screened by whole exome sequencing (WES) on Illumina platform. Possibly disease-associated variants were determined by filtering based on minor allele frequency, predicted pathogenicity and were verified by Sanger sequencing followed by segregation analysis.
Ophthalmological findings of the affected family members included salt-and-pepper retinopathy, attenuation of the arterioles and generalized rod-cone dysfunction. Atypical for RP features included mottled macula at early age, peripapillary sparing of RPE and relatively preserved photoreceptor layer considering ERG loss. In addition, the affected children presented with uniform systemic features such as short stature, prominent facial features and learning disabilities. Both parents had no ophthalmological or systemic symptoms. Analysis of WES data under a recessive model of inheritance identified only 4 genes as possible candidates for the causal gene in this family. After multimodal analysis, only the retinol dehydrogenase 11 (RDH11) gene remained as the plausible candidate for the ocular phenotype, since all affected children were compound heterozygotes for two stop mutations in RDH11.
Deleterious mutations in RDH11, a gene long considered a strong candidate for RP, are causal in a family with arRP. The same mutations could also be responsible for syndromic features in affected individuals in this family.
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