June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Molecular diagnostic yield for Black/African American participants in eyeGENE®
Author Affiliations & Notes
  • Nia Moore
    National Eye Institute, Bethesda, Maryland, United States
  • Melissa Reeves
    National Eye Institute, Bethesda, Maryland, United States
  • Kerry E Goetz
    National Eye Institute, Bethesda, Maryland, United States
  • Bin Guan
    National Eye Institute, Bethesda, Maryland, United States
  • Ehsan Ullah
    National Eye Institute, Bethesda, Maryland, United States
  • Kari Branham
    University of Michigan, Ann Arbor, Michigan, United States
  • K. Thiran Jayasundera
    University of Michigan, Ann Arbor, Michigan, United States
  • Santa J Tumminia
    National Eye Institute, Bethesda, Maryland, United States
  • Robert B. Hufnagel
    National Eye Institute, Bethesda, Maryland, United States
  • Footnotes
    Commercial Relationships   Nia Moore None; Melissa Reeves None; Kerry Goetz None; Bin Guan None; Ehsan Ullah None; Kari Branham None; K. Thiran Jayasundera None; Santa Tumminia None; Robert Hufnagel None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3079. doi:
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      Nia Moore, Melissa Reeves, Kerry E Goetz, Bin Guan, Ehsan Ullah, Kari Branham, K. Thiran Jayasundera, Santa J Tumminia, Robert B. Hufnagel; Molecular diagnostic yield for Black/African American participants in eyeGENE®. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3079.

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

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Abstract

Purpose : Black and African American (AA) individuals are underrepresented in genomic research. This may lead to disparity in genetic testing in Black/AA individuals with inherited retinal diseases (IRDs). To improve clinical genetic diagnostics and variant classification, we assessed genotypes in a cohort of Black/AA participants in the NIH/NEI National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE®).

Methods : Clinical genetic testing data was analyzed for participants enrolled in eyeGENE® who were reported by the referring clinical organization as Black/AA (n=517). To calculate diagnostic yield and allele enrichment, individual genotypes were assessed as unsolved, solved, or partially solved for molecular diagnosis, correlating gene with clinical diagnosis and family history, and variant classifications were compared across the cohort using ACMG criteria.

Results : Within Black/AA participants in eyeGENE®, there were 27 clinical diagnoses, with 78% having a diagnosis of Stargardt Disease (n=179), Retinitis Pigmentosa and other Retinal degenerations (n=171), or Cone-Rod Dystrophy (n=51). In total, 746 unique variants from 189 genes were identified by clinical genetic testing. Diagnostic yield was 38% (196/517), with an additional 20% partially solved (105/517), compared to 62% diagnostic yield in the overall eyeGENE® cohort. The most commonly observed variants in this cohort were ABCA4:c.6320G>A (p.Arg2107His) (VUS =16, Pathogenic =27, Benign =1) and ABCA4:c.3602T>G (p.Leu1201Arg) (VUS =14, Pathogenic/Likely Pathogenic =17, Likely Benign =1). Both variants have conflicting interpretations in ClinVar. The ABCA4 p.Arg2107His variant appears enriched in the eyeGENE® Black/AA cohort, while p.Leu1201Arg is not enriched. Reclassification of p.Arg2107His to Pathogenic for all instances improved overall diagnostic yield to 41% (211/517).

Conclusions : The diagnostic yield in this cohort of Black/AA individuals with IRD is lower than the whole eyeGENE® cohort, highlighting an inequity in information available for variant classification. Recurrent observations of VUS further support pathogenicity by allele frequency enrichment, typically permitting reclassification from VUS to Likely Pathogenic/Pathogenic. Broad efforts are needed to systematically increase underrepresented individual participation in genetic research studies and to re-classify variants across the Black/AA population to improve diagnostic yield.

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

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