Elsevier

Ophthalmology

Volume 123, Issue 5, May 2016, Pages 1143-1150
Ophthalmology

Original article
Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease

Presented at: the UK Eye Genetics Group Annual Meeting, May 15, 2015, Manchester, England, and the European Human Genetics Conference, June 9, 2015, Glasgow, Scotland, and the American Society of Human Genetics Annual Meeting, October 8, 2015, Baltimore, MD.
https://doi.org/10.1016/j.ophtha.2016.01.009Get rights and content
Under a Creative Commons license
open access

Purpose

To compare the efficacy of whole genome sequencing (WGS) with targeted next-generation sequencing (NGS) in the diagnosis of inherited retinal disease (IRD).

Design

Case series.

Participants

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.

Main Outcome Measures

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.

Abbreviations and Acronyms

CI
confidence interval
IRD
inherited retinal disease
MCGM
Manchester Centre for Genomic Medicine
NGS
next-generation sequencing
RP
retinitis pigmentosa
SNV
single nucleotide variant
WES
whole exome sequencing
WGS
whole genome sequencing

Cited by (0)

Supplemental material is available at www.aaojournal.org.

Financial Disclosure(s): The author(s) have made the following disclosure(s): R.L. and R.T.: Employees of Complete Genomics, Inc.

Funded by the Fight For Sight, RP Fighting Blindness, the Biotechnology and Biological Sciences Research Council, and the Manchester Biomedical Research Centre. We acknowledge contributions from the UK Inherited Retinal Disease Consortium.

Author Contributions:

Conception and design: Ellingford, Bhaskar, Leach, Bayliss, Nemeth, Black

Data collection: Ellingford, Barton, Bhaskar, Williams, Sergouniotis, O’Sullivan, Perveen, Hall, Bishop, Tearle, Nemeth, Black

Analysis and interpretation: Ellingford, Barton, Sergouniotis, Lamb, Newman, Roberts, Ramsden, Black

Obtained funding: none

Overall responsibility: Ellingford, Barton, Bhaskar, Williams, Sergouniotis, O'Sullivan, Lamb, Perveen, Hall, Newman, Bishop, Roberts, Leach, Tearle, Bayliss, Ramsden, Nemeth, Black