Establishing Standardized Criteria to Improve the Interpretation of Genetic Testing for Ocular Disorders

Abstract

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.