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Koji M. Nishiguchi, Makoto Nakamura, Mineo Kondo, Shinji Ueno, Tetsuhiro R. Yasuma, Rick Tearle, Jacques Beckmann, Hiroko Terasaki, Eliot L. Berson, Carlo Rivolta; Whole Genome Analysis Of 16 Unrelated Patients With Autosomal Recessive Retinitis Pigmentosa Reveals Novel Single-Base And Large Structural Genomic Mutations. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4524.
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To analyze the whole genome sequence of 16 unrelated patients with autosomal recessive retinitis pigmentosa (arRP) and identify both small-scale mutations and large structural variants that could be responsible for this disease.
Whole-genome allelic sequencing was performed according to the Complete Genomics procedure on DNA of 16 unrelated patients with arRP: 8 from the United States and 8 from Japan. Publicly available sequences obtained with the same methods from 69 healthy individuals were also analyzed. Patients from the USA were from diverse ethnic backgrounds including those of East Asian, mixed European, Hispanic, and Caribbean ancestry. Bioinformatic analyses were mostly performed by the use of scripts developed in-house. Targeted re-sequencing was performed by the Sanger method on DNA from cohorts of ethnically matched patients with arRP or healthy individuals.
Among the set of known arRP-associated genes, we detected diallelic pathogenic mutations in 7 different genes (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in 8 patients. Five of them were from the USA while 3 were from Japan. Fourteen out of the 16 mutations identified were novel. Two pathogenic structural variants affecting one or more exons, likely invisible to standard screening methods or even to exome-sequencing, accounted for arRP in 2 patients.
With full-genome data, we could integrate many sources of information at once (e.g. SNP genotypes, phasing, etc.) and precisely recognize causative mutations among numerous genomic DNA variants in single patients, as opposed to classical family-based methods. We found that the systematic analysis of structural variants is important for conducting comprehensive screening, which may account for some genetically unsolved cases.
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