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Christina Gerth-Kahlert, Amit Tiwari, Angela Bahr, James V.M. Hanson, Wolfgang Berger; Genotype - phenotype analysis in a family with autosomal dominant retinitis pigmentosa and a mutation in SNRNP200.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2767.
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Mutations in SNRNP200 are associated with autosomal dominant retinitis pigmentosa (RP). We performed whole exome sequencing (WES) in a patient with RP and evaluated the phenotype characteristics in the patient's family. which shows a potentially pathogenic mutation in the SNRNP200 gene.
The index patient and 3 of the affected family members received a comprehensive eye examination with a detailed retinal functional (ffERG; mfERG) and morphological (OCT; autofluorescence) assessment. Genetic testing was performed by WES in the index patient using an Illumina NextSeq 500 platform. Sequence data were compared with the reference human genome hg19. Alignment and variant calling was performed at the Base Space Onsite. Annotation of variants was done using Alamut-Batch and visualized by Alamut-Viewer. Potentially disease-associated sequence variants in retinal disease genes were then confirmed by Sanger sequencing in additional affected and one unaffected family members.
All patients described nyctalopia as the first presenting symptom during childhood to young adulthood. Visual acuity ranged from 20/30 (age 35yrs) to 20/200 (age 68yrs). 2/4 patients are highly myopic. FfERG responses were non-recordable, mfERG responses were severely diminished. Retinal morphology showed typical signs of RP with severely diminished outer retinal layers on OCT. One obligate carrier does not report visual symptoms but was not yet available for testing. Genetic analysis revealed a missense variant in exon 25 of the SNRNP200 gene as the most likely disease-associated sequence variation in the index patient (c.3260C>T, p.Ser1087Leu). The same mutation was previously reported as pathogenic, is predicted to be strongly pathogenic and is also predicted to affect canonical splicing of exon 25. Subsequent segregation analysis in additional affected and unaffected family members supported this interpretation. In addition, the index patient had novel compound heterozygous variants in the MYO7A gene (p.Tyr1580Cys and p.Glu1794Lys) and previously disease-associated heterozygous variants in CRB1 (p.Arg1331His) and AIPL1 (p.Arg324Leu). These variants may act as disease modifiers.
An amino acid substitution in SNRNP200 appears to cause a typical RP phenotype with intra-familial variability and incomplete penetrance in the investigated family.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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