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

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 AllenRuth 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, Andrew R Webster, F Lucy Raymond, NIHR-BioResource Rare Diseases Consortium, Sarah Westbury

Research output: Contribution to journalArticle (Academic Journal)

143 Citations (Scopus)
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Abstract

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 languageEnglish
Pages (from-to)75-90
Number of pages16
JournalAmerican Journal of Human Genetics
Volume100
Issue number1
DOIs
Publication statusPublished - 5 Jan 2017

Keywords

  • 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
  • Journal Article

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