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Phenotypic diversity in autosomal-dominant cone-rod dystrophy elucidated by adaptive optics retinal imaging
  1. Hongxin Song1,2,
  2. Ethan A Rossi3,
  3. Edwin Stone4,
  4. Lisa Latchney5,
  5. David Williams2,6,
  6. Alfredo Dubra7,
  7. Mina Chung5
  1. 1 Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual SciencesNational Engineering Research Center for Ophthalmic Equipment, Beijing, China
  2. 2 University of Rochester, Center for Visual Science, Rochester, New York, USA
  3. 3 Department of Ophthalmology, Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  4. 4 Department of Ophthalmology andVisual Sciences, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
  5. 5 University of Rochester, Flaum Eye Institute, Rochester, New York, USA
  6. 6 University of Rochester, Institute of Optics, Rochester, New York, USA
  7. 7 Department of Ophthalmology, Stanford University, Palo Alto, California, USA
  1. Correspondence to Dr Mina Chung, Flaum Eye Institute, University of Rochester, 601 Elmwood Ave Box 659, Rochester, NY 14642, USA; mina_chung{at}urmc.rochester.edu and Dr Hongxin Song, Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, National Engineering Research Center for Ophthalmic Equipment, 17 Hou Gou Lane, Beijing 100005, China; songhongxin2012{at}163.com

Abstract

Purpose Several genes causing autosomal-dominant cone-rod dystrophy (AD-CRD) have been identified. However, the mechanisms by which genetic mutations lead to cellular loss in human disease remain poorly understood. Here we combine genotyping with high-resolution adaptive optics retinal imaging to elucidate the retinal phenotype at a cellular level in patients with AD-CRD harbouring a defect in the GUCA1A gene.

Methods Nine affected members of a four-generation AD-CRD pedigree and three unaffected first-degree relatives underwent clinical examinations including visual acuity, fundus examination, Goldmann perimetry, spectral domain optical coherence tomography and electroretinography. Genome-wide scan followed by bidirectional sequencing was performed on all affected participants. High-resolution imaging using a custom adaptive optics scanning light ophthalmoscope (AOSLO) was performed for selected participants.

Results Clinical evaluations showed a range of disease severity from normal fundus appearance in teenaged patients to pronounced macular atrophy in older patients. Molecular genetic testing showed a mutation in in GUCA1A segregating with disease. AOSLO imaging revealed that of the two teenage patients with mild disease, one had severe disruption of the photoreceptor mosaic while the other had a normal cone mosaic.

Conclusions AOSLO imaging demonstrated variability in the pattern of cone and rod cell loss between two teenage cousins with early AD-CRD, who had similar clinical features and had the identical disease-causing mutation in GUCA1A. This finding suggests that a mutation in GUCA1A does not lead to the same degree of AD-CRD in all patients. Modifying factors may mitigate or augment disease severity, leading to different retinal cellular phenotypes.

  • dystrophy
  • imaging
  • retina
  • genetics
  • degeneration

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Contributors HS made substantial contributions to the acquisition and analysis of the adaptive optics imaging data and drafting the work. EAR made substantial contributions to the acquisition and analysis of the adaptive optics imaging data and drafting the work. ES made substantial contributions to the acquisition and analysis of the genetics data and critically revised the work. LL made substantial contributions to the acquisition and analysis of the adaptive optics imaging data and drafting the work. DW made substantial contributions to the interpretation of the adaptive optics imaging data and critically revised the work. AD made substantial contributions to the design of the adaptive optics study, interpretation of the adaptive optics imaging data and critically revised the work. MC made substantial contributions to the conception or design of the work, the interpretation of data, drafting and critically revising the work.

  • Funding This work was supported by the National Eye Institute (EY021786, EY021669, EY001319, EY014375, and EY004367), Research to Prevent Blindness, Fight for Sight(ER) and the Burroughs Wellcome Fund (AD).

  • Competing interests DW is an inventor on licensed patents pertaining to the adaptive optics ophthalmoscope that are owned by the University of Rochester.

  • Patient consent Obtained.

  • Ethics approval Research Subjects Review Board at the University of Rochester.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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