title: Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease.
abstract: OBJECTIVE
  To compare the efficacy of whole genome sequencing (WGS) with targeted next-generation sequencing (NGS) in the diagnosis of inherited retinal disease (IRD).
  
  
  METHODS
  Case series.
  
  
  METHODS
  A total of 562 patients diagnosed with IRD.
  
  
  METHODS
  We performed a direct comparative analysis of current molecular diagnostics with WGS. We retrospectively reviewed the findings from a diagnostic NGS DNA test for 562 patients with IRD. A subset of 46 of 562 patients (encompassing potential clinical outcomes of diagnostic analysis) also underwent WGS, and we compared mutation detection rates and molecular diagnostic yields. In addition, we compared the sensitivity and specificity of the 2 techniques to identify known single nucleotide variants (SNVs) using 6 control samples with publically available genotype data.
  
  
  METHODS
  Diagnostic yield of genomic testing.
  
  
  RESULTS
  Across known disease-causing genes, targeted NGS and WGS achieved similar levels of sensitivity and specificity for SNV detection. However, WGS also identified 14 clinically relevant genetic variants through WGS that had not been identified by NGS diagnostic testing for the 46 individuals with IRD. These variants included large deletions and variants in noncoding regions of the genome. Identification of these variants confirmed a molecular diagnosis of IRD for 11 of the 33 individuals referred for WGS who had not obtained a molecular diagnosis through targeted NGS testing. Weighted estimates, accounting for population structure, suggest that WGS methods could result in an overall 29% (95% confidence interval, 15-45) uplift in diagnostic yield.
  
  
  CONCLUSIONS
  We show that WGS methods can detect disease-causing genetic variants missed by current NGS diagnostic methodologies for IRD and thereby demonstrate the clinical utility and additional value of WGS.
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; Institute of Human Development, University of Manchester, Manchester, United Kingdom.
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Ellingford
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Barton
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Bhaskar
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Williams
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; Institute of Human Development, University of Manchester, Manchester, United Kingdom; Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Panagiotis I
authors.initials: PI
authors.lastname: Sergouniotis
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; Institute of Human Development, University of Manchester, Manchester, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: Institute of Population Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Janine A
authors.initials: JA
authors.lastname: Lamb
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; Institute of Human Development, University of Manchester, Manchester, United Kingdom.
authors.forename: Rahat
authors.initials: R
authors.lastname: Perveen
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Georgina
authors.initials: G
authors.lastname: Hall
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; Institute of Human Development, University of Manchester, Manchester, United Kingdom.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Institute of Human Development, University of Manchester, Manchester, United Kingdom; Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Bishop
authors.affiliation: Centre for Biostatistics, Institute of Population Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Roberts
authors.affiliation: Complete Genomics, Inc., Mountain View, California.
authors.forename: Rick
authors.initials: R
authors.lastname: Leach
authors.affiliation: Complete Genomics, Inc., Mountain View, California.
authors.forename: Rick
authors.initials: R
authors.lastname: Tearle
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Bayliss
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Ramsden
authors.affiliation: Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Nemeth
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; Institute of Human Development, University of Manchester, Manchester, United Kingdom; Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom. Electronic address: graeme.black@manchester.ac.uk.
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
mesh_terms: D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005260:Female; D016678:Genome; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques; D020641:Polymorphism, Single Nucleotide; D012164:Retinal Diseases / Q000235:genetics*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA