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Paola Benaglio, Koji M. Nishiguchi, Marta Corton, Almudena Avila-Fernandez, Rosa Riveiro-Alvarez, Carmen Ayuso, Carlo Rivolta; Exome Sequencing In Individual Patients With Recessive Retinal Degeneration As A Tool For Mutation And Disease Gene Discovery. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4519.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the efficacy of exome sequencing as a diagnostic and gene discovery tool in unrelated patients with recessive retinal degeneration (RD).
Fourteen families from Spain were ascertained. The DNA from the index patient of each family was processed by exome-capture / Next-Generation Sequencing, followed by in silico data analyses developed in house. The majority of these patients resulted to be negative to on-chip screening for previously-reported mutations. Co-segregation analyses and validation of DNA changes were done by Sanger sequencing.
Despite the high number of novel DNA variants and the elevated technical noise that are present in every human exome sequence, we successfully identified causative mutations in the index patients from 8 different families, and likely pathogenic changes in 2 others. Our analytical pipeline did not integrate genotype information from other members of these pedigrees and was based on simple data filtering procedures. Specifically, we detected pathogenic DNA variants (70% novel mutations) in the genes RP1, USH2A, CHM, and ABCA4, responsible for retinitis pigmentosa, choroideremia, and recessive Stargardt / cone-rod dystrophy cases. For one specific patient with retinitis pigmentosa extending exome analysis to other members of the pedigree allowed revealing a potentially novel disease gene.
Exome sequencing in individual patients with recessive RD revealed pathogenic gene defects in ~60-80% of the cases examined. In conjunction with specific data processing and filtering, this technique could represent a powerful and cost-effective tool for molecular diagnostics and genetic research, even in cases for which no genotypes from family members are available.
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