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.
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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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