June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Identifying critical diagnostic features that distinguish ABCA4 disease from its Mendelian phenocopies
Author Affiliations & Notes
  • Winston Lee
    Genetics & Development, Columbia University Irving Medical Center, New York, New York, United States
    Ophthalmology, Columbia University Irving Medical Center, New York, New York, United States
  • Jana Zernant
    Ophthalmology, Columbia University Irving Medical Center, New York, New York, United States
  • Takayuki Nagasaki
    Ophthalmology, Columbia University Irving Medical Center, New York, New York, United States
  • Stephen H Tsang
    Ophthalmology, Columbia University Irving Medical Center, New York, New York, United States
    Pathology & Cell Biology, Columbia University Irving Medical Center, New York, New York, United States
  • Rando Allikmets
    Ophthalmology, Columbia University Irving Medical Center, New York, New York, United States
    Pathology & Cell Biology, Columbia University Irving Medical Center, New York, New York, United States
  • Footnotes
    Commercial Relationships   Winston Lee None; Jana Zernant None; Takayuki Nagasaki None; Stephen Tsang Emendo Biotherapeutics, Code C (Consultant/Contractor), Nanoscope Therapeutics, Code C (Consultant/Contractor), Abeona Therapeutics, Code F (Financial Support); Rando Allikmets None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 3745 – F0166. doi:
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      Winston Lee, Jana Zernant, Takayuki Nagasaki, Stephen H Tsang, Rando Allikmets; Identifying critical diagnostic features that distinguish ABCA4 disease from its Mendelian phenocopies. Invest. Ophthalmol. Vis. Sci. 2022;63(7):3745 – F0166.

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

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Abstract

Purpose : To identify the most critical diagnostic features that differentiate ABCA4 disease from its numerous monogenic phenocopying retinal disorders.

Methods : Clinical and demographic features from a large cohort of 407 genetically-confirmed ABCA4 disease patients were compared to 68 patients harboring causal variants in various retinal dystrophy genes known to phenocopy ABCA4. Clinical data analyzed in both groups included detailed clinical and family histories, multimodal retinal imaging (fundus photographs, 488-nm, 521-nm and 787-nm AF, spectral domain-optical coherence tomography) and full-field electroretinogram (ffERG) testing.

Results : We identified 6 predominant phenotypes of ABCA4 disease that exhibit significant clinical overlap with approximately 43 different retinal dystrophy genes. In milder phenotypes such as bull’s eye maculopathy (BEM), ABCA4 was most effectively distinguished from genes such as CRX, GUCY2D, RPGR and PROM1 by the age at clinical presentation (p<0.001). Age was also a critical factor between ABCA4 and RP1L1-associated occult macular dystrophy (OMD); however, non-retinal features such as the presence of nystagmus were considered for early onset OMD-associated genes like CNGA3 and CNGB3. In the most advanced clinical stages characterized by widespread degeneration across the posterior pole, differential diagnoses extended to non-maculopathy genes such as RPE65 and CERKL. Differentiating factors included identifying degenerative progression patterns and delayed peripapillary atrophy although symptomatic history was singularly most effective (p<0.001). Several genes such as PRPH2 and ROM1 phenocopied multiple pathognomonic features of ABCA4 disease and required more in-depth characterization such as fleck morphology and total area of the spared foveal region (p<0.00001). With some exceptions, ffERG, visual acuity and family history were the least effective considerations for diagnostic accuracy.

Conclusions : The clinical spectrum of ABCA4 is phenocopied, to varying degrees, by over 40 different retinal dystrophy genes. The list of differential diagnoses changes according to the various clinical stages of ABCA4. In the vast majority of cases, individual demographic considerations such as the age at presentation or symptomatic history are sufficient for making an accurate diagnosis.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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