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Validation of copy number variation analysis for next-generation sequencing diagnostics.
Ellingford, Jamie M; Campbell, Christopher; Barton, Stephanie; Bhaskar, Sanjeev; Gupta, Saurabh; Taylor, Rachel L; Sergouniotis, Panagiotis I; Horn, Bradley; Lamb, Janine A; Michaelides, Michel; Webster, Andrew R; Newman, William G; Panda, Binay; Ramsden, Simon C; Black, Graeme Cm.
Afiliação
  • Ellingford JM; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
  • Campbell C; Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
  • Barton S; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
  • Bhaskar S; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
  • Gupta S; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
  • Taylor RL; Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, India.
  • Sergouniotis PI; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
  • Horn B; Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
  • Lamb JA; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
  • Michaelides M; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
  • Webster AR; Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
  • Newman WG; Moorfields Eye Hospital NHS Foundation Trust, London, UK.
  • Panda B; UCL Institute of Ophthalmology, Department of Genetics, London, UK.
  • Ramsden SC; Moorfields Eye Hospital NHS Foundation Trust, London, UK.
  • Black GC; UCL Institute of Ophthalmology, Department of Genetics, London, UK.
Eur J Hum Genet ; 25(6): 719-724, 2017 06.
Article em En | MEDLINE | ID: mdl-28378820
Although a common cause of disease, copy number variants (CNVs) have not routinely been identified from next-generation sequencing (NGS) data in a clinical context. This study aimed to examine the sensitivity and specificity of a widely used software package, ExomeDepth, to identify CNVs from targeted NGS data sets. We benchmarked the accuracy of CNV detection using ExomeDepth v1.1.6 applied to targeted NGS data sets by comparison to CNV events detected through whole-genome sequencing for 25 individuals and determined the sensitivity and specificity of ExomeDepth applied to these targeted NGS data sets to be 100% and 99.8%, respectively. To define quality assurance metrics for CNV surveillance through ExomeDepth, we undertook simulation of single-exon (n=1000) and multiple-exon heterozygous deletion events (n=1749), determining a sensitivity of 97% (n=2749). We identified that the extent of sequencing coverage, the inter- and intra-sample variability in the depth of sequencing coverage and the composition of analysis regions are all important determinants of successful CNV surveillance through ExomeDepth. We then applied these quality assurance metrics during CNV surveillance for 140 individuals across 12 distinct clinical areas, encompassing over 500 potential rare disease diagnoses. All 140 individuals lacked molecular diagnoses after routine clinical NGS testing, and by application of ExomeDepth, we identified 17 CNVs contributing to the cause of a Mendelian disorder. Our findings support the integration of CNV detection using ExomeDepth v1.1.6 with routine targeted NGS diagnostic services for Mendelian disorders. Implementation of this strategy increases diagnostic yields and enhances clinical care.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article