June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Establishing Standardized Criteria to Improve the Interpretation of Genetic Testing for Ocular Disorders
Author Affiliations & Notes
  • Kristy Lee
    Department of Genetics, University of North Carolina System, Chapel Hill, North Carolina, United States
  • Emily Place
    Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Radha Ayyagari
    Departments of Ophthalmology and Pathology, University of California San Diego, La Jolla, California, United States
  • Rui Chen
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Kerry Goetz
    National Eye Institute, Bethesda, Maryland, United States
  • Robert B Hufnagel
    National Eye Institute, Bethesda, Maryland, United States
  • Linda Reis
    Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Susanne Roosing
    Radboud Universiteit, Nijmegen, Gelderland, Netherlands
  • Emmanuelle Souzeau
    Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia
  • Patrick Yu-Wai-Man
    Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, Cambridge, Cambridgeshire, United Kingdom
    Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom
  • Brian Mansfield
    Foundation Fighting Blindness Inc, Columbia, Maryland, United States
  • Janey L Wiggs
    Department of Ophthalmology, Harvard Medical School, Mass Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Kristy Lee, None; Emily Place, None; Radha Ayyagari, None; Rui Chen, None; Kerry Goetz, None; Robert Hufnagel, None; Linda Reis, None; Susanne Roosing, None; Emmanuelle Souzeau, None; Patrick Yu-Wai-Man, None; Brian Mansfield, None; Janey Wiggs, None
  • Footnotes
    Support  NHGRI Grant U41HG009650
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1566. doi:
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      Kristy Lee, Emily Place, Radha Ayyagari, Rui Chen, Kerry Goetz, Robert B Hufnagel, Linda Reis, Susanne Roosing, Emmanuelle Souzeau, Patrick Yu-Wai-Man, Brian Mansfield, Janey L Wiggs; Establishing Standardized Criteria to Improve the Interpretation of Genetic Testing for Ocular Disorders. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1566.

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

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Purpose : In 2014 the American Academy of Ophthalmology recommended patients receive genetic testing for inherited eye diseases. This recommendation, along with sponsored genetic testing programs, has greatly increased utilization of genetic testing. While genetic testing can inform a clinical diagnosis and determine the inheritance pattern, the genetic basis of ocular diseases is diverse, requiring large comprehensive gene panels. This it can also lead to many candidate variants per patient, increasing the risk of a genetic misdiagnosis. Differing standards on variant calls, especially around variants of uncertain significance (VUS), can lead to different genetic interpretations.

The Clinical Genome Resource (ClinGen) is an international consortium funded primarily by the National Human Genome Research Institute of NIH to promote the standardization of gene and variant interpretation to improve clinical care. The Ocular Clinical Domain Working Group (CDWG) within ClinGen was established in 2019 to address this need for inherited eye diseases.

Methods : The CDWG convened an executive committee of clinicians and researchers with expertise in retinal, glaucoma and neuro-ophthalmology disorders. Expert panels (EP) are being developed to tackle gene curation (GCEP) to assess the association between a particular gene and a disease phenotype and variant curation (VCEP) to assess the pathogenicity of variants within selected genes with respect to a specific phenotype. The variant curation process has been given US FDA recognition.

Results : We established 2 GCEP’s (Retina and Glaucoma/Neuro) and 4 VCEP’s (OPA1, Glaucoma, LCA, X-linked retinal dystrophy) with an additional ABCA4 VCEP in development. The membership, curation protocols and gene curation results are available on the ClinGen website (https://clinicalgenome.org/). Variant classifications and supporting data will be available in the NIH ClinVar database.

Conclusions : By assessing the strength of gene/disease associations, standardizing FDA recognized gene-specific variant curation guidelines, sharing genomic data amongst expert members and incorporating data from existing disease databases, the number of VUS will decrease, improving the value of genetic testing as a diagnostic tool and guiding patient eligibility for the growing clinical pipeline of genetic therapies for inherited retinal diseases.

This is a 2021 ARVO Annual Meeting abstract.


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