%0 Journal Article
%T Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease
%A Alba Sanchis-Juan
%A Andrew£¿R. Webster
%A Angela F. Brady
%A Anthony T. Moore
%A Christopher Penkett
%A Detelina Grozeva
%A Dorothy A. Thompson
%A Dragana Josifova
%A Elaine Murphy
%A Eleanor Dewhurst
%A Elisabeth Rosser
%A Emma Clement
%A Emma Wakeling
%A Gavin Arno
%A Genevieve Wright
%A Jane Hurst
%A Jenny Carmichael
%A Joan Paterson
%A Jonathan Stephens
%A Karyn Megy
%A Kathleen Stirrups
%A Keren J. Carss
%A Louise Allen
%A Manali Chitre
%A Maria Bitner-Glindzicz
%A Marie Erwood
%A Michel Michaelides
%A NIHR-BioResource Rare Diseases Consortium
%A Richard H. Scott
%A Robert E. MacLaren
%A Robert H.H. Henderson
%A Roberta Rizzo
%A Ruth Armstrong
%A Samantha Malka
%A Sarah Hull
%A Vincent Plagnol
%A Willem H. Ouwehand
%J Archive of "American Journal of Human Genetics".
%D 2017
%R 10.1016/j.ajhg.2016.12.003
%X 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%) 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
%K retinal dystrophy
%K whole-genome sequence
%K copy-number variants
%K rare sequence variant
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223092/