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


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.

SUBMITTER: Carss KJ 

PROVIDER: S-EPMC5223092 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Carss Keren J KJ   Arno Gavin G   Erwood Marie M   Stephens Jonathan J   Sanchis-Juan Alba A   Hull Sarah S   Megy Karyn K   Grozeva Detelina D   Dewhurst Eleanor E   Malka Samantha S   Plagnol Vincent V   Penkett Christopher C   Stirrups Kathleen K   Rizzo Roberta R   Wright Genevieve G   Josifova Dragana D   Bitner-Glindzicz Maria M   Scott Richard H RH   Clement Emma E   Allen Louise L   Armstrong Ruth R   Brady Angela F AF   Carmichael Jenny J   Chitre Manali M   Henderson Robert H H RHH   Hurst Jane J   MacLaren Robert E RE   Murphy Elaine E   Paterson Joan J   Rosser Elisabeth E   Thompson Dorothy A DA   Wakeling Emma E   Ouwehand Willem H WH   Michaelides Michel M   Moore Anthony T AT   Webster Andrew R AR   Raymond F Lucy FL  

American journal of human genetics 20161229 1


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%) i  ...[more]

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