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Jacque L. Duncan, Mili Navani, Sangeetha Vishveswaraiah, Harini V. Gudiseva, Pauline Lee, Terry Gaasterland, Radha Ayyagari; Exome Analysis Identified A Novel Mutation In A Family With Recessive Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4523.
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To describe the clinical phenotype and identify the molecular basis of disease in a family with autosomal recessive retinal degeneration (RD).
The phenotype in 7 members of a consanguineous family with 3 siblings affected with autosomal recessive RD was characterized with visual acuity, visual fields and fundus examination. Affected individuals were further evaluated with Goldmann perimetry, fundus photos, optical coherence tomography, and full-field electroretinography (ERG). Exome was captured using Nimblegen SeqCap EZ V2.0 probes and sequenced on llumina HiSeq. Reads were mapped to reference hg19 using a tiered strategy developed to maximize mapping fidelity and minimize false positive variant calls. SNP calls and annotations were performed with published protocols. Confirmation of mutation and segregation analysis was performed using dideoxy sequencing.
Three affected female siblings were diagnosed with RD. Both parents, 4 sisters and one brother were unaffected. Unaffected parents and 2 sisters had normal eye examinations. Three affected sisters had photophobia, decreased color vision and night blindness beginning during adolescence. The affected members showed loss of the outer retinal layers and retinal pigment epithelium in the macula, although retinal structure was preserved at the fovea in the 2 youngest patients. Patients showed progressive loss of visual acuity ranging from 20/30 to counting fingers, severe color vision loss, constricted visual fields, paracentral and central scotomas and unrecordable ERG. Analysis detected 24,037 exome SNPs in one affected member, of which 3,622 SNPs were rare and potentially damaging to encoded proteins. Further analysis revealed a novel homozygous nonsense change in the PCDH21 gene, which would result in premature truncation of the protein, or nonsense mediated decay of the transcript. Mutation analysis confirmed segregation of this sequence change with RD in this family.
Exome analysis revealed a novel PCDH21 nonsense mutation segregating with severe, progressive retinal degeneration associated with severe central vision loss by the 3rd decade of life.
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