June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Evaluating the clinical validity of the gene:disease relationship in inherited retinal disorders
Author Affiliations & Notes
  • Laryssa Huryn
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, United States
  • William Hankey
    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Jennifer Goldstein
    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Panagiotis Sergouniotis
    The University of Manchester, Manchester, United Kingdom
  • Kristy Lee
    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Gavin Arno
    Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
  • Robert B. Hufnagel
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, United States
  • Footnotes
    Commercial Relationships   Laryssa Huryn None; William Hankey None; Jennifer Goldstein None; Panagiotis Sergouniotis None; Kristy Lee None; Gavin Arno None; Robert Hufnagel None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4502. doi:
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      Laryssa Huryn, William Hankey, Jennifer Goldstein, Panagiotis Sergouniotis, Kristy Lee, Gavin Arno, Robert B. Hufnagel; Evaluating the clinical validity of the gene:disease relationship in inherited retinal disorders. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4502.

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

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Abstract

Purpose : To outline progress in reviewing the clinical validity of genes implicated in inherited retinal disorders by the Clinical Genome Resource (ClinGen) Retina Gene Curation Expert Panel (GCEP).

Methods : The Retina GCEP is using an established ClinGen framework to evaluate >250 genes. Specifically, it reviews the inheritance pattern(s), phenotypic variability and molecular mechanism(s) associated with each gene and decides if a gene implicated in multiple disease entities requires multiple curations (or if these entities represent parts of the same phenotypic spectrum). Genetic and experimental evidence is systematically reviewed to evaluate each gene:disease relationship.

Results : Between 2020 and 2022 the ClinGen Retina GCEP evaluated the clinical validity of 58 gene:disease relationships. Among reviewed genes, 42 were associated with a single disease entity in the biomedical literature while 12 were associated with ≥2 entities. Of these 12 genes, 4 had split curations for two clinically distinct entities while the remaining 8 were associated with entities with adequately overlapping clinical features to be accounted for by one curation. An illustrative case is GPR143 which has historically been linked with X-linked congenital Nystagmus 6 and Nettleship-Falls type Ocular albinism, type I. In this case, given the high degree of phenotypic overlap and the similar molecular mechanism and inheritance pattern, a single curation was undertaken. To standardize the nomenclature for the relevant entities, the Retina GCEP supports a gene-first nomenclature system (with previous terms included as synonyms for search/indexing purposes). After reviewing the published clinical features and discussion with subject matter experts, “GPR143-related foveal hypoplasia with or without albinism” was identified as the unifying terminology that most accurately describe the full phenotypic spectrum linked to this gene.

Conclusions : Inherited retinal disorders exhibit significant clinical and genetic heterogeneity and a standardized framework to assess the validity of gene:disease relationships is critical to building a better understanding of the link between molecules and phenotype. Such knowledge is expected to ultimately inform therapeutic approaches, improving patient care. Notably, a gene-first nomenclature system has enabled us to unify multiple entities that represent parts of a single phenotypic spectrum.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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