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Caroline Van Cauwenbergh, Frauke Coppieters, Sarah De Jaegere, Julie De Zaeytijd, Bart Leroy, Elfride De Baere; Exome Sequencing Identifies a Novel RP1 Mutation in a Belgian Family with Autosomal Dominant Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3355.
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© ARVO (1962-2015); The Authors (2016-present)
To identify the underlying genetic cause in a multigenerational Belgian family with autosomal dominant retinitis pigmentosa (adRP) using genome-wide linkage analysis and exome sequencing.
Five affected and eight unaffected individuals from a four-generation Belgian adRP family were clinically evaluated. They underwent genome-wide linkage analysis using BeadChips (Illumina) and multipoint linkage analysis (Merlin, dominant model, 95% penetrance, disease allele frequency of 0.0001). Exome sequencing was performed in two affected individuals (TruSeq Exome Enrichment Kit, HiSeq, Illumina). The CLC Genomics Workbench (CLC bio) was employed for read mapping and variant calling. Linkage regions and RetNet genes were used for filtering of exome variants.
GW linkage analysis revealed two regions with a maximum LOD score of 1.7. As to the exome data, 11.3/12.7 and 12.9/14.5 million reads could be mapped against the human genome reference sequence, resulting in an average coverage of 87.8 and 99.3 respectively. Integrated linkage- and RetNet gene-based filtering of exome data revealed a heterozygous RP1 change in both patients: p.Leu749fs and p.Leu750fs respectively. Of note, variant calling failed to correctly call this change. Sanger sequencing confirmed following mutation: c.2245_2248delinsTGAG (p.Leu749X). This mutation was found to co-segregate with disease, one unaffected individual excepted, suggesting incomplete penetrance. This indel mutation, replacing nucleotides CTCA by their reverse complement TGAG, creates a premature stop codon that may lead to a truncated protein. The mutation, present in a hotspot region in exon 4, belongs to the ‘Class II’ mutations, which are frequently reported nonsense mediated decay-insensitive truncations, with a net dominant negative effect.
Combined linkage-based filtering of exome data revealed a novel RP1 mutation in a Belgian pedigree with adRP. Our study expands the spectrum of RP1 Class II mutations leading to adRP with incomplete penetrance. Interestingly, the findings of this study can be used as a starting point for further research on modifiers influencing RP1 expression.
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