June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Evaluating the diagnostic yield of whole genome sequencing in genetic eye disease
Author Affiliations & Notes
  • Samantha Malka
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
  • Elena Schiff
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
  • Hannah Knight
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
  • Genevieve Wright
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
  • Ainoa Cordoba Gimenez
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
  • Michel Michaelides
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Patrick Yu-Wai-Man
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
    University of Cambridge, Cambridge, Cambridgeshire, United Kingdom
  • Omar Abdul Rahman Mahroo
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Gavin Arno
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Andrew Webster
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Mariya Moosajee
    Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Footnotes
    Commercial Relationships   Samantha Malka, None; Elena Schiff, None; Hannah Knight, None; Genevieve Wright, None; Ainoa Cordoba Gimenez, None; Michel Michaelides, None; Patrick Yu-Wai-Man, None; Omar Mahroo, None; Gavin Arno, None; Andrew Webster, None; Mariya Moosajee, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1556. doi:
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      Samantha Malka, Elena Schiff, Hannah Knight, Genevieve Wright, Ainoa Cordoba Gimenez, Michel Michaelides, Patrick Yu-Wai-Man, Omar Abdul Rahman Mahroo, Gavin Arno, Andrew Webster, Mariya Moosajee; Evaluating the diagnostic yield of whole genome sequencing in genetic eye disease. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1556.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The introduction of whole genome sequencing (WGS) within the UK National Health Service (NHS) represents a global shift from targeted panel testing to genomic analysis. We performed a retrospective analysis of patients with a range of genetic eye disorders who had WGS to evaluate its utility.

Methods : Data was gathered from 1669 families from the ocular genetics service at Moorfields Eye Hospital, who underwent WGS through the UK Genomics England 100,000 Genomes Project. Patients were grouped into 4 categories based on their primary diagnosis: posterior segment disorders (including retinal dystrophies and optic neuropathies); anterior segment abnormalities (including bilateral congenital cataract, primary congenital glaucoma, and corneal dystrophies); ocular malformations (including microphthalmia, anophthalmia and coloboma); and albinism/nystagmus. A targeted virtual gene panel was applied to the WGS data in the first instance, followed by re-analysis incorporating off-panel variant interrogation and expert review with a multidisciplinary team (consisting of bioinformaticians, ophthalmologists specialising in genetic eye disease, clinical geneticist, and genetic counsellors) for unsolved cases.

Results : Overall, WGS yielded a molecular diagnosis in 55.8% of cases (931/1669). Solve rates grouped by diagnosis, family history, ethnicity and prior testing can be found in Table 1.

In 183 families (11.0% of all families; 19.6% of solved families), the genetic diagnosis was missed by initial laboratory analysis, but found through re-analysis by our multidisciplinary team. This was achieved by having expertise in ocular phenotypes, relaxing variant filtering, applying additional gene panels and interrogating copy number variation and non-coding variants.

Conclusions : A multidisciplinary, case-specific approach to genetic testing utilizing unbiased genome sequencing technology has yielded an overall molecular solve rate of 55.8% of patients in this large mixed cohort. It is uniquely possible to further scrutinise WGS data as new discoveries are made enabling additional molecular diagnoses without the need for additional expensive molecular investigations.

This is a 2021 ARVO Annual Meeting abstract.

 

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