The retinal phenotype associated with the frequent, synonymous c.783G>A mutation in CDHR1

Abstract

Purpose : Variants in CDHR1, coding for a cadherin strongly expressed in photoreceptors, are an increasingly recognized cause of recessively inherited retinal degeneration. Herein, we describe the retinal phenotype in patients with the common c.783G>A variant in CDHR1.

Methods : Eight consecutive adult patients with retinal degeneration and biallelic variants in CDHR1 were included. Each patient underwent full ophthalmic clinical evaluation and multi-modal retinal imaging (Spectralis HRA-OCT; Heidelberg Engineering, Germany), including fundus photography, fundus autofluorescence imaging, and spectral domain optical coherence tomography. Fundus tracking perimetry (MAIA, Centervue, Padova, Italy) was performed in three patients. Longitudinal blue autofluorescence imaging (up to 11 years) was available for four patients. The study adheres to the tenets of the Declaration of Helsinki. Institutional Review Board approval and written patient consent were obtained.

Results : Three groups of CDHR1 genotypes were recognized: Group 1 (5 patients) were homozygous for the c.783G>A CDHR1 variant, Group 2 (2 patients) were compound heterozygous for the c.783G>A CDHR1 variant and a truncating CDHR1 mutation, Group 3 (1 patient) was included for comparison with two truncating mutations in CDHR1. All patients were asymptomatic in the first 4 decades of life. Patients in group 1 demonstrate symptoms attributable to macular dysfunction in the 5^th decade of life. Patients in group 2 and 3 also reported nyctalopia. In group 1, the earliest manifestation is of a bulls-eye macular appearance with foveal sparing. Later stages closely resembled peripherin-2 (PRPH2)-related central areolar choroidal dystrophy (CACD) on all imaging modalities, including fundus autofluorescence. The progressive macular degeneration leads to severe loss of visual acuity over a period of 10 years from first symptoms with relative preservation of the peripheral retina. In contrast, group 2 & 3 demonstrate a widespread retinal degeneration. The retinal phenotype in c.783G>A homozygotes resembles autosomal dominant, peripherin-2 (PRPH2)-related CACD.

Conclusions : This study shows the broad phenotypic presentation of CDHR1-related retinal degeneration. Recessive retinal degeneration due to homozygosity for the mild c.783G>A mutation is clinically indistinguishable from PRPH2-related CACD.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.