Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome

ABSTRACT

Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here, we characterize the clinical phenotype of disease caused by variants in CEP78, CEP250, ARSG, and ABHD12.

Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease-causing variants in CEP78, CEP250, ARSG, or ABHD12.

CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL. ARSG variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. ABHD12-related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe.

This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients who have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.

KEYWORDS:

• Atypical usher syndrome
• CEP78
• cep250
• ARSG
• ABHD12

Acknowledgments

The authors would like to thank Delphine Blain, ScM, MBA - Certified Genetic Counselor for support with this project.

Disclosure of interest

The authors report no conflict of interest.

Additional information

Funding

This work is funded by the National Institutes of Health [P30EY010572, K08EY026650, 5P30CA013696, U01EY030580, U54OD020351, R24EY028758, R01EY009076, R24EY027285, 5P30EY019007, R01EY018213, R01EY024698, R01EY024091, R01EY026682, R21AG050437NIH intramural research fund], the Research to Prevent Blindness [unrestricted grant for Casey Eye Institute, unrestricted grant for UCLA], the Foundation Fighting Blindness [CD-NMT-0714–0648, CD-CL-0617-0727-HSC], New York Regional Research Center Grant [PPA-1218-0751-COLU], Jonas Children’s Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, the Schneeweiss Stem Cell Fund, New York State [SDHDOH01-C32590GG-3450000], Nancy & Kobi Karp, the Crowley Family Funds, the Rosenbaum Family Foundation, Alcon Research Institute, and the Gebroe Family Foundation, Harold and Pauline Price Foundation, Nina Abrams Fund, ames V. Bastek, M.D. Hereditary Retinal Disease Research Program, the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001, and the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The sponsors or funding organizations had no role in the design or conduct of this research; Alcon Research Institute; CAPES [Finance Code 001]; Foundation Fighting Blindness [CD-CL-0617-0727-HSC,CD-NMT-0714–0648]; National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology; Crowley Family Funds; Nina Abrams Fund; Harold and Pauline Price Foundation; Gebroe Family Foundation; Nancy & Kobi Karp;Schneeweiss Stem Cell Fund [SDHDOH01-C32590GG-3450000]; Jonas Children’s Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory; James V. Bastek, M.D. Hereditary Retinal Disease Research Program; Rosenbaum Family Foundation; New York Regional Research Center Grant [PPA-1218-0751-COLU]; Research to Prevent Blindness [Unrestricted Grant for Casey Eye Institute,Unrestricted Grant for UCLA].