Phenotype Analysis of Retinal Dystrophies in Light of the Underlying Genetic Defects: Application to Cone and Cone-Rod Dystrophies.

Elise Boulanger-Scemama,Fiona Boyard,Aline Antonio,Jean-Paul Saraiva,Said El Shamieh,Isabelle Audo,Christina Zeitz,José-Alain Sahel,Christelle Michiels,Saddek Mohand-Saïd,Mélanie Letexier,Vanessa Démontant,Christel Condroyer

doi:10.3390/ijms20194854

Abstract

Phenotypes observed in a large cohort of patients with cone and cone-rod dystrophies (COD/CORDs) are described based on multimodal retinal imaging features in order to help in analyzing massive next-generation sequencing data. Structural abnormalities of 58 subjects with molecular diagnosis of COD/CORDs were analyzed through specific retinal imaging including spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (BAF/IRAF). Findings were analyzed with the underlying genetic defects. A ring of increased autofluorescence was mainly observed in patients with CRX and GUCY2D mutations (33% and 22% of cases respectively). “Speckled” autofluorescence was observed with mutations in three different genes (ABCA4 64%; C2Orf71 and PRPH2, 18% each). Peripapillary sparing was only found in association with mutations in ABCA4, although only present in 40% of such genotypes. Regarding SD-OCT, specific outer retinal abnormalities were more commonly observed in particular genotypes: focal retrofoveal interruption and GUCY2D mutations (50%), foveal sparing and CRX mutations (50%), and outer retinal atrophy associated with hyperreflective dots and ABCA4 mutations (69%). This study outlines the phenotypic heterogeneity of COD/CORDs hampering statistical correlations. A larger study correlating retinal imaging with genetic results is necessary to identify specific clinical features that may help in selecting pathogenic variants generated by high-throughput sequencing.

Highlights

Cone and cone-rod dystrophies (COD/CORDs) refer to a heterogeneous group of inherited retinal disorders (IRDs), characterized predominantly by cone impairment
DWiesciunsvseiostnigated a large series of CODs and CORDs patients, and we carefully evaluated their clinicalWcheairnavcetestriigsatitcesduasilnarggreestienriaelsimofaCgOinDg,s wanhdicCh OwReDres fpuarttiheenrtsr,ealantdedwteoctahre fguellnyeetivcadluiagtendosthise.ir clinical characteristics using retinal imaging, which were further related to the genetic diagnosis
Unlike mutations in ABCA4, PROM1, or CRX, GUCY2D mutations were always associated with fundus alterations solely restricted to the macula

Summary

Introduction

Cone and cone-rod dystrophies (COD/CORDs) refer to a heterogeneous group of inherited retinal disorders (IRDs), characterized predominantly by cone impairment. They are the most common cause of hereditary cone dysfunction, with a prevalence of 1:40,000 [1]. They are characterized by progressive central vision loss, photophobia, and color vision abnormalities in childhood or early adulthood. ERG responses may be undetectable, making the distinction between CORD and severe rod-cone dystrophy (RCD) difficult, and somewhat artificial, in these cases. Progressive COD/CORDs need to be distinguished from cone dysfunction syndromes, which are stationary and congenital with normal rod function [3]. COD/CORDs often present as an isolated disease, but they can be part of a syndrome as in Bardet–Biedl or Jalili syndromes or spinocerebellar ataxia 7 [1,4,5]

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