Abstract
Purpose :
The clinical presentation of Stargardt macular dystrophy(STGD) often overlaps with other cone-rod dystrophies in families from Southern India. It is important to understand the genetic basis of such clinical, phenotypic diversity. Therefore, we evaluated the role of genotypic variations on disease presentation, progression, patient counselling and management of disease in a STGD cohort
Methods :
50 affected and 94 unaffected family members of 39 families were studied with institutional ethics approval. Visual and retinal assessment (using fundus imaging, FAF imaging and OCT), whole exome sequencing and functional categorization of mutations were performed for all patients and families. Based on flecks-like deposits with peripapillary sparing confirmed by fundus imaging, foveomacular atrophy, FAF confirmation and supplementary features noted on OCT, families were sub-classified according to Fishman grading. Based on presence or lack of concordance between the clinical phenotype and observed genotype four additional groups were constructed. Electrophysiological tests were done based on clinical indication. A set of mutations were cloned and studied for expression in HEK293T cells
Results :
Fishman classification accommodated 41 subjects, while non-classical presentations were observed in 9 subjects. Foveomacular atrophy with peripapillary sparing without flecks were found in non-classical STGD cases. Of these, ABCA4 mutation was seen in 1 case while novel genotypes were found in 8 cases. Overall, 44 mutations in 10 genes were identified in this study. We found 33 mutations in ABCA4 gene, 2 mutations each in CRB1 and C2orf71 gene, and 1 mutation each in additional 7 genes. Within the mutations of ABCA4, 8 point mutations based on their location within protein domains were selected for functional analysis. Expression of these 8 mutant ABCA4 proteins in HEK293T cells showed instability of varying degrees compared to WT ABCA4 protein. Compared to trans-membrane domain mutants, instability was more prominent in extracellular domain mutants. Phenotypic variations among probands is partly explained by these observations
Conclusions :
Novel variants and genes associated with STGD, and non-classical clinical presentation of STGD with genotypic variations identified in our study may form a basis for patient selection for gene and cell therapy trials in future
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.