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Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Keren Carss, G Arno, M Erwood, J Stephens, A Sanchis-Juan, S Hull, K Megy, D Grozeva, E Dewhurst, S Malka, V Plagnol, C Penkett (+28 others)
2017

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Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%)
more » ... ndividuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
doi:10.17863/cam.7967 fatcat:yjjxys5enbddblbpfmyu2k4dyi
Citation

Keren Carss, G Arno, M Erwood, J Stephens, A Sanchis-Juan, S Hull, K Megy, D Grozeva, E Dewhurst, S Malka, V Plagnol, C Penkett, K Stirrups, R Rizzo, G Wright, D Josifova, M Bitner-Glindzicz, RH Scott, E Clement, L Allen, R Armstrong, AF Brady, J Carmichael, M Chitre, RHH Henderson, J Hurst, RE MacLaren, E Murphy, J Paterson, E Rosser, DA Thompson, E Wakeling, WH Ouwehand, M Michaelides, AT Moore, NIHR-BioResource Rare Diseases Consortium, AR Webster, Lucy Raymond, Apollo-University Of Cambridge Repository, Apollo-University Of Cambridge Repository. "Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease." (2017)