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Yajing Xie, Stephen H Tsang, Carmen Ayuso, Winston Lee, Shalini N Jhangiani, Tomasz Gambin, Bo Yuan, James R Lupski, Rando Allikmets; CRX mutations in patients with phenotypes resembling Stargardt disease. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3256.
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To determine the disease-causing genes and mutations in patients with phenotypes resembling Stargardt disease (STGD) but harboring no ABCA4 mutations and to perform detailed analysis of the subpopulation of these patients with CRX mutations.
Ophthalmic examination, including fundus photography, autofluorescence (AF) imaging, and spectral-domain optical coherence tomography (SD-OCT), was performed on 10 patients from 3 families and 2 sporadic cases. The ABCA4 gene was sequenced in all affected individuals with negative results. Subsequently, affected and unaffected members from each family and sporadic cases were subjected to whole exome sequencing (WES) on Illumina platform. Possibly disease-associated variants were determined by filtering based on minor allele frequency and predicted pathogenicity. Identified CRX variants were verified by Sanger sequencing followed by segregation analysis.
Ophthalmological findings included central continuous macular atrophy in a bull’s eye pattern and high density AF rings surrounding the atrophic area, consistent with the phenotypes most often associated with ABCA4 mutations. While no ABCA4 mutations were detected in any patient, the WES analysis identified 3 new deleterious CRX mutations, p.S150*, p.D219fs, p.Y221fs, and 2 missense variants, R41W and p.G122D, which had been associated with a retinal disease before. The CRX variants segregated with the disease in 2/3 families when allowing for incomplete penetrance. In one family the previously described as pathogenic CRX variant p.G122D did not segregate with the disease and PRPF31 was identified as the likely causal gene in this family instead. Altogether, 4/5 CRX variants were considered disease-causing in this study.
Mutations in CRX are not infrequent in patients presenting with phenotypes usually associated with ABCA4 mutations, such as STGD and Bull’s Eye Maculopathy. Incomplete penetrance and co-segregation with variants in other candidate genes highlight the complex inheritance pattern associated with CRX variation and the need for careful analysis of causality in retinal diseases.
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