Structural and functional characterization of an individual with the M285R hypomorphic allele.

BACKGROUND

Disease-causing variants in the gene are associated with "cone dystrophy with supernormal rod responses," a rare autosomal recessive retinal dystrophy. There is no previous report of hypomorphic variants in the disease.

MATERIAL AND METHODS

Medical history, genetic testing, ocular examination, high-resolution retinal imaging including adaptive optics scanning light ophthalmoscopy (AOSLO), and functional assessments.

RESULTS

A 16-year-old male with mild cone-rod dystrophy presented with reduced central vision and photophobia. Genetic testing showed two variants in , c.614_617dupAGCG (p.207AlafsTer166) and c.854T>G (p.Met285Arg), the latter which was previously considered benign. Electrophysiological assessment revealed the pathognomic electroretinogram waveforms associated with -retinopathy. Optical coherence tomography showed discrete focal ellipsoid zone disruption, while fundus autofluorescence was normal. Non-waveguiding cones corresponding to areas of loss of photoreceptor integrity were visible on adaptive optics scanning light ophthalmoscopy. Retinal sensitivity and fixation were relatively preserved, with a demonstrable deterioration after 14 months of follow-up.

CONCLUSIONS

We provide functional and structural evidence that the variant M285R is disease-causing if associated with a loss-of-function variant. To the best of our knowledge, this is the first hypomorphic allele reported in .