How multimodal retinal imaging can help with Next Generation Sequencing interpretation: the example of cone and cone-rod dystrophies

Abstract

Purpose : To perform multimodal retinal imaging in a large cohort of patients with cone and cone-rod dystrophies (CD/CRD) and draw schematic genotype-phenotype correlations to help filtering and interpreting massive data from Next Generation Sequencing (NGS).

Methods : In a previous study, NGS was applied to 95 CD/CRD cases, based on functional abnormalities, which identified the genetic defects in 62.1% of cases. Among these, we selected 58 subjects and further analyzed structural abnormalities through multimodal imaging including fundus autofluorescence and SD-OCT. Findings were correlated with underlying genetic defects.

Results : Macular hypoautofluorescence was present in 90% of cases with varying patterns from subtle foveal changes to widespread confluent hypoautofluorescent areas. A ring of increased autofluorescence was mainly associated with CRX and GUCY2D mutations (33% and 22% of cases respectively). "Speckled" autofluorescence was associated with mutations in 3 different genes (ABCA4 64%, C2Orf71 and PRPH2, 18% each). In addition, a peripapillary sparing was only found in association with mutations in ABCA4, without being constant (40%). Regarding SD-OCT, the interdigitation zone was absent in all cases whereas the ellipsoid was abnormal in 94% of cases. Specific outer retinal abnormalities were more commonly associated with particular genotypes: focal retrofoveal interruption and GUCY2D mutations (50%), foveal sparing and CRX mutations (50%), outer retinal atrophy associated with hyperreflective dots and ABCA4 mutations (69%).

Conclusions : This study outlines the phenotypic heterogeneity of CD/CRD with difficulties drawing statistical correlations. However, multimodal retinal imaging analysis confronted with genetic results allowed the identification of clinical features that may help selecting pathogenic variants generated by high throughput sequencing. Thus, in case of a ring of hyper-autofluorescence, the association with foveal sparing on SD-OCT is more likely due to CRX mutations whereas the lack of foveal sparing is more likely due to GUCY2D mutations. In case of "speckled" autofluorescence the absence of peripapillary sparing is more likely due to mutations on PRPH2 or C2Orf71 whereas a preserved peripapillary autofluorescence and hyperreflective dots on SD-OCT are most likely due to ABCA4 mutations.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.