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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%) 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.

Original publication

DOI

10.1016/j.ajhg.2016.12.003

Type

Journal article

Journal

Am J Hum Genet

Volume

100

Pages

75 - 90

Keywords

copy-number variants, rare sequence variant, retinal dystrophy, whole-genome sequence, Adaptor Proteins, Signal Transducing, Alleles, Base Sequence, Choroideremia, DNA Mutational Analysis, Ethnic Groups, Exome, Female, Genes, Recessive, Genetic Variation, Genome, Human, Humans, Introns, Male, Mutation, Rare Diseases, Retinal Diseases