Advance Molecular Testing Paves the Road to Clear Cut Diagnosis of Hereditary Retinal Dystrophies

Retinal Dystrophies (RDs) are genetically complex group of congenital eye disorders caused by mutations in over 300 genes. Genetic diversity of RDs articulates the overlap of symptoms and clinical variation of disease entities, manipulating the accuracy of clinical diagnosis. Genetic technologies have shown a promising potential in diagnosis and possibility of targeted treatments. Introduction of multi-gene panels and Whole Exome Sequencing (WES) technologies has significantly boosted the detection of candidate genes paving the way for effective genetic counseling as well as risk assessment for further conceptions. Furthermore, it will help to predict the clinical course and aid disease management which is the central importance of patients’ professional and social lives.Methods: Peripheral blood samples were collected from the patients and their family members upon written informed consent. WES was initially performed on the proband. Variants were analyzed using various bioinformatics databases and software. Genomic DNA was analyzed by PCR and Sanger sequencing using specific primers encompassing the exon and intronic boundaries of the identified variants in ABCA4, NDP, MERTK, CRB1, LRP5 & TTC8 genes. Genotype-phenotype correlation and segregation analysis was conducted among relatives to determine the pathogenicity of the variants. All patients underwent post genetic counseling.Results: Iranian families with previous family history of retinal disorders were investigated. Molecular approaches identified 7 novel deleterious mutations; c.6316C> T (p.R2106C) and c.1819G> C (p.G607R) in ABCA4, c.200G> T (p.G67V) and c.269G> C (p.R90L) in NDP, c.2182T> C (p.S728P) in CRB1, c.2707dupA (p.S902fs*) in LRP5 and c.462_465delTTTG (p.F156fs*56) in TTC8 genes. One family, who referred for PND, did not reveal any deleterious variant.Conclusion: This study highlights the importance of meticulous clinical diagnosis for life style management of visually disabled patients. The need to uncover genetic diagnosis of retinal disorders is particularly important in the development of gene therapy-based treatments as well as prenatal diagnosis (PND) and recent advances in reproductive options. Therefore, amalgamation of precise clinical and advanced molecular diagnosis may open new horizons for therapeutic services and aiding future decision-making and assisting with research. It is anticipated that this approach may minimize the risk of hereditary retinal diseases in relevant Iranian families.