June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Dual Molecular Diagnoses in Patients with Inherited Retinal Degenerations
Author Affiliations & Notes
  • Marta Stevanovic
    Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
  • Kaitlin O’Connell
    Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
  • Priya Gupta
    Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
  • John Simmons Borchert
    Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
  • Jason Comander
    Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
  • Emily Place
    Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
  • Rachel M Huckfeldt
    Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Marta Stevanovic None; Kaitlin O’Connell None; Priya Gupta None; John Borchert None; Jason Comander None; Emily Place None; Rachel Huckfeldt None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4635. doi:
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    • Get Citation

      Marta Stevanovic, Kaitlin O’Connell, Priya Gupta, John Simmons Borchert, Jason Comander, Emily Place, Rachel M Huckfeldt; Dual Molecular Diagnoses in Patients with Inherited Retinal Degenerations. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4635.

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

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Abstract

Purpose : To highlight individuals with inherited retinal degenerations (IRD) whose likely underlying genetic explanation for retinal disease involves more than one gene. These findings may have prognostic implications, impact genetic counseling, and affect eligibility for gene-specific clinical trials.

Methods : Patients seen at Massachusetts Eye and Ear between 2020 and 2022 who had multiple potential genetic solutions for their clinical diagnosis were identified. Genetic testing was performed using commercial retinal dystrophy panels with variant classification following the American College of Medical Genetics criteria; only variants that were pathogenic (P) or likely pathogenic (LP) were included. The results of genetic testing were compared to clinical data, and family members were assessed when possible.

Results : Four patients were identified: two with macular dystrophies and two with retinitis pigmentosa (RP). Patient 1 (P1), who had a multigenerational family history of PRPH2-associated pattern dystrophy (PD), had anatomic disruption throughout the posterior pole with corresponding functional impact in contrast to the limited macular abnormalities in his asymptomatic affected parent. Genetic testing identified the familial PRPH2 variant (P) and two variants in ABCA4 (both P) in trans. Patient 2 (P2) had clinical findings of PD and was identified to have a PRPH2 variant (LP) and two ABCA4 variants (P, LP). There was no family history of IRD, and family members were not available for segregation analysis. Patient 3 (P3) had RP with two CNGA1 variants in trans (both P) as well as a RHO variant (P). There was no family history of RP. Patient 4 (P4), who had a diagnosis of Usher syndrome type 2, had two variants in USH2A (both P) and a PRPH2 variant (LP). There was no family history of retinal disease; familial assessments were pending.

Conclusions : This cohort demonstrates the value of broad genetic testing in explaining phenotypic variation within families (P1) and assessing familial risk even in the setting of presumed recessive disease (P4). These cases also illustrate the ambiguity introduced if segregation analysis cannot be performed (P2) and the challenges of understanding how coexisting variants in multiple genes impact clinical phenotype and prognosis even if phase is known (P3).

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

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