Abstract
Purpose
Recent advances in sequencing technologies have enabled radical and rapid progress in the genetic diagnosis of inherited retinal disorders (IRDs). Although the list of gene variations continues to grow, it lacks the genetic etiology of ethnic groups like South Asians. Differences in racial backgrounds and consanguinity add to genetic heterogeneity and phenotypic overlaps.
Methods
This retrospective study includes documented data from the Gen-Eye clinic from years 2014 to 2019. Medical records and pedigrees of 591 IRD patients of Indian origin and genetic reports of 117 probands were reviewed. Genotype–phenotype correlations were performed to classify as correlating, non-correlating and unsolved cases.
Results
Among the 591 patients, we observed a higher prevalence of clinically diagnosed retinitis pigmentosa (38.9%) followed by unspecified diagnoses (28.5%). Consanguinity was reported to be high (55.6%) in this cohort. Among the variants identified in 117 probands, 36.4% of variants were pathogenic, 19.2% were likely pathogenic, and 44.4% were of uncertain significance. Among the pathogenic and likely pathogenic variants, autosomal recessive inheritance showed higher prevalence. About 35% (41/117) of cases showed genotype–phenotype correlation. Within the correlating cases, retinitis pigmentosa and Stargardt disease were predominant. Novel variants identified in RP, Stargardt, and LCA are reported here.
Conclusion
This first-of-a-kind report on an Indian cohort contributes to existing knowledge and expansion of variant databases, presenting relevant and plausible novel variants. Phenotypic overlap and variability lead to a differential diagnosis and hence a clear genotype–phenotype correlation helps in precise clinical confirmation. The study also emphasizes the importance of genetic counselling and testing for personalized vision care in a tertiary eye hospital.
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Data availability
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
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Acknowledgements
Patients and their families visiting the Gen-Eye clinic and Narayana Nethralaya. Gen-Eye clinic coordinators—Naina Kumari and Reshma Varamballi for their efforts in patient management. Dr. Swaminathan Sethu and Dr. Arkasubhra Ghosh for their critical review and support. The Medgenome team for providing commercial next generation sequencing services and Anbu Kayalvizhi for variant data analysis.
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Contributions
AG conceptualized the study design, CG and RR are co-first authors, CG, GPM, and AG wrote the manuscript, RR prepared images and tables, RP maintained patient records. AV, PB, TBM, and SB referred patients to the Gen-Eye Clinic based on clinical diagnosis for clinical and genetic correlations. We thank KBS for providing facilities and GKM for the genetics expertise.
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Ethical clearance (EC Ref No: C/2021/08/03) for this retrospective study has been obtained by the Narayana Nethralaya Ethics Review Board.
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Chitra Gopinath and Ramya Rompicherla are co-first authors
Supplementary Information
Supplementary Figure 1.
Decision of IRD diagnosis and patient inclusion criteria in the study. (PNG 865 kb)
Supplementary table 1.
Patient details, clinical diagnoses, genetic test results, clinical and genetic correlation statuses of 117 patients who underwent genetic testing. (XLSX 37 kb)
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Gopinath, C., Rompicherla, R., Mathias, G.P. et al. Inherited retinal disorders: a genotype–phenotype correlation in an Indian cohort and the importance of genetic testing and genetic counselling. Graefes Arch Clin Exp Ophthalmol 261, 2003–2017 (2023). https://doi.org/10.1007/s00417-022-05955-5
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DOI: https://doi.org/10.1007/s00417-022-05955-5