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

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.

The Clinical Spectrum and Disease Course of DRAM2 Retinopathy

“…Including this report, 19 unique variants in DRAM2 associated with retinopathy caused were identified (Table 2). Among these, 42% (8/19) Macular photoreceptor loss, normal peripheral retina (29). Maculopathy, mid-peripheral degenerations (35).…”

“…The hyperautofluorescent ring may be found in several IRDs and usually delineates the border between the preserved and affected retina. In cone dystrophy (CD)/CRD, the retina is affected inside the ring, whereas in RCD (retinitis pigmentosa (RP)), the retina is affected outside the ring [29][30][31]. The source of hyperautofluorescence is thought to be photoreceptor outer segment loss overlaying the still intact RPE, resulting in the increased detection of the normal RPE autofluorescence due to the decreased blockage of photoreceptors [13].…”

“…The source of hyperautofluorescence is thought to be photoreceptor outer segment loss overlaying the still intact RPE, resulting in the increased detection of the normal RPE autofluorescence due to the decreased blockage of photoreceptors [13]. Another cause of increased autofluorescence is possibly the increased accumulation of lipofuscin in the degenerating photoreceptor inner segments and/or the RPE, potentially contributing to photoreceptor damage [29,30,32].…”

CNGB1 ‐related rod‐cone dystrophy: A mutation review and update

“…The SW‐FAF showed the presence of a preserved central area of autofluorescence surrounded by a ring of hyperautofluorescence that clearly demarked the advancement of the peripheral outer retinal atrophy (Figures 2 and 3). This sign may represent an abnormal perifoveal accumulation of lipofuscin in the RPE due to increased outer segment dysgenesis (Lima et al, 2009; Robson et al, 2006) or a window defect caused by the atrophic alterations of the photoreceptors above a still intact RPE (Boulanger‐Scemama et al, 2019; Khateb, Nassisi, et al, 2019). In a recent study employing quantitative fundus autofluorescence, it was shown that SW‐AF in the ring reflects an actual increase in AF intensity within the ring relative to corresponding areas in the healthy retina.…”

Targeted next generation sequencing and family survey enable correct genetic diagnosis in CRX associated macular dystrophy – a case report

“…It is clear however that the presence of BEM is not pathognomic for CRX , as BEM has been described in association with sequence variants in CRX , ABCA4 and GUCY2D [ 16 ]. The spared fovea has been seen in patients with CRX mutations before, with Boulanger-Scemama et al reporting that half of their cohort of CRX patients had a spared fovea [ 17 ].…”