• Keren J Carss, Gavin Arno, Marie Erwood, Jonathan Stephens, Alba Sanchis-Juan, Sarah Hull, Karyn Megy, Detelina Grozeva, Eleanor Dewhurst, Samantha Malka, Vincent Plagnol, Christopher Penkett, Kathleen Stirrups, Roberta Rizzo, Genevieve Wright, Dragana Josifova, Maria Bitner-Glindzicz, Richard H Scott, Emma Clement, Louise Allen, Ruth Armstrong, Angela F Brady, Jenny Carmichael, Manali Chitre, Robert H H Henderson, Jane Hurst, Robert E MacLaren, Elaine Murphy, Joan Paterson, Elisabeth Rosser, Dorothy A Thompson, Emma Wakeling, Willem H Ouwehand, Michel Michaelides, Anthony T Moore, NIHR-BioResource Rare Diseases Consortium, Andrew R Webster, and F Lucy Raymond.
• Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
• Am. J. Hum. Genet. 2017 Jan 5; 100 (1): 75-90.

AbstractInherited 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%) individuals. 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 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.Copyright © 2017. Published by Elsevier Inc.

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