Whole-exome sequencing and molecular dynamics confirm pathogenicity of a novel SLC6A6 mutation in Leber congenital amaurosis
Abstract Introduction Inherited retinal diseases (IRDs) are a clinically and genetically heterogenous group where the robust advancement of next-generation sequencing technologies has facilitated genotype-assisted diagnosis. Leber congenital amaurosis (LCA) is a severe form of inherited retinal dyst...
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2025-02-01
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| Series: | Egyptian Journal of Medical Human Genetics |
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| Online Access: | https://doi.org/10.1186/s43042-025-00659-x |
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| author | Srikrupa N. Natarajan Samdani Ansar Sarangapani Sripriya Sen Parveen Ravi Gupta Umashankar Vetrivel Mathavan Sinnakarupan |
| author_facet | Srikrupa N. Natarajan Samdani Ansar Sarangapani Sripriya Sen Parveen Ravi Gupta Umashankar Vetrivel Mathavan Sinnakarupan |
| author_sort | Srikrupa N. Natarajan |
| collection | DOAJ |
| description | Abstract Introduction Inherited retinal diseases (IRDs) are a clinically and genetically heterogenous group where the robust advancement of next-generation sequencing technologies has facilitated genotype-assisted diagnosis. Leber congenital amaurosis (LCA) is a severe form of inherited retinal dystrophy that causes congenital blindness or near-blindness with a global prevalence of 3 per 100,000 live births.It is characterized by a loss of vision at birth or within the first few years of life with overlapping phenotypes to many syndromic and non-syndromic IRDs. With India's rich genetic heterogeneity, WES is a valuable tool for uncovering novel gene mutations linked to LCA. This genetic diversity expands our understanding of the disease's spectrum in the Indian population. Methods In our previous study, 92 Indian LCA families were screened through targeted resequencing, and 80% of probands exhibited mutations in known genes. Hence, the remaining 20% probands with additional family members (n = 40) were subjected to whole-exome sequencing. An in-house standard bioinformatics pipeline was used for variant calling and annotation. Homology modeling (Modeller-9.23) and molecular simulation were performed on an identified SLC6A6 gene variant that has not yet been associated with LCA to investigate its potential pathogenicity. Results Disease-causing pathogenic variants were identified in 15/20 families (75%) across 11 genes with 33% variants being novel. Among the identified 17 variants in 15 families, 35% were missense, 29% nonsense, 29% frameshift and 6% splice variants. Segregation analysis, control screening and in silico predictions confirmed the variant’s pathogenicity. All variants were classified as pathogenic according to ACMG guidelines. Homology modeling and molecular simulation in the membrane system for the p.Pro82Leu mutant in SLC6A6 protein showed significant modification in helical characteristics around the TM2 helix in the mutant, which could potentially hinder the regular function and cause disruption in taurine transport across the membrane leading to the disease. Conclusion Taurine being an essential amino acid for photoreceptor development and maintenance, our study suggests that mutation identified in SLC6A6 gene may cause LCA. This is the first report of SLC6A6 gene association with LCA and also the first case report in the Indian population. |
| format | Article |
| id | doaj-art-2f5795c4aa1f41d0891a5078c3e72a92 |
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| series | Egyptian Journal of Medical Human Genetics |
| spelling | doaj-art-2f5795c4aa1f41d0891a5078c3e72a922025-08-20T03:10:49ZengSpringerOpenEgyptian Journal of Medical Human Genetics2090-24412025-02-0126111210.1186/s43042-025-00659-xWhole-exome sequencing and molecular dynamics confirm pathogenicity of a novel SLC6A6 mutation in Leber congenital amaurosisSrikrupa N. Natarajan0Samdani Ansar1Sarangapani Sripriya2Sen Parveen3Ravi Gupta4Umashankar Vetrivel5Mathavan Sinnakarupan6SNONGC Department of Genetics and Molecular Biology, Vision Research FoundationFormerly With Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research FoundationSNONGC Department of Genetics and Molecular Biology, Vision Research FoundationFormerly With Medical Research Foundation, Shri Bhagwan Mahavir Vitreoretinal ServicesMedGenome Labs Pvt. LtdDepartment of Health Research, (Govt. of India), National Institute of Traditional Medicine, Indian Council of Medical ResearchSNONGC Department of Genetics and Molecular Biology, Vision Research FoundationAbstract Introduction Inherited retinal diseases (IRDs) are a clinically and genetically heterogenous group where the robust advancement of next-generation sequencing technologies has facilitated genotype-assisted diagnosis. Leber congenital amaurosis (LCA) is a severe form of inherited retinal dystrophy that causes congenital blindness or near-blindness with a global prevalence of 3 per 100,000 live births.It is characterized by a loss of vision at birth or within the first few years of life with overlapping phenotypes to many syndromic and non-syndromic IRDs. With India's rich genetic heterogeneity, WES is a valuable tool for uncovering novel gene mutations linked to LCA. This genetic diversity expands our understanding of the disease's spectrum in the Indian population. Methods In our previous study, 92 Indian LCA families were screened through targeted resequencing, and 80% of probands exhibited mutations in known genes. Hence, the remaining 20% probands with additional family members (n = 40) were subjected to whole-exome sequencing. An in-house standard bioinformatics pipeline was used for variant calling and annotation. Homology modeling (Modeller-9.23) and molecular simulation were performed on an identified SLC6A6 gene variant that has not yet been associated with LCA to investigate its potential pathogenicity. Results Disease-causing pathogenic variants were identified in 15/20 families (75%) across 11 genes with 33% variants being novel. Among the identified 17 variants in 15 families, 35% were missense, 29% nonsense, 29% frameshift and 6% splice variants. Segregation analysis, control screening and in silico predictions confirmed the variant’s pathogenicity. All variants were classified as pathogenic according to ACMG guidelines. Homology modeling and molecular simulation in the membrane system for the p.Pro82Leu mutant in SLC6A6 protein showed significant modification in helical characteristics around the TM2 helix in the mutant, which could potentially hinder the regular function and cause disruption in taurine transport across the membrane leading to the disease. Conclusion Taurine being an essential amino acid for photoreceptor development and maintenance, our study suggests that mutation identified in SLC6A6 gene may cause LCA. This is the first report of SLC6A6 gene association with LCA and also the first case report in the Indian population.https://doi.org/10.1186/s43042-025-00659-xNext-generation sequencingSLC6A6Leber congenital amaurosisWhole-exome sequencingHomology modeling |
| spellingShingle | Srikrupa N. Natarajan Samdani Ansar Sarangapani Sripriya Sen Parveen Ravi Gupta Umashankar Vetrivel Mathavan Sinnakarupan Whole-exome sequencing and molecular dynamics confirm pathogenicity of a novel SLC6A6 mutation in Leber congenital amaurosis Egyptian Journal of Medical Human Genetics Next-generation sequencing SLC6A6 Leber congenital amaurosis Whole-exome sequencing Homology modeling |
| title | Whole-exome sequencing and molecular dynamics confirm pathogenicity of a novel SLC6A6 mutation in Leber congenital amaurosis |
| title_full | Whole-exome sequencing and molecular dynamics confirm pathogenicity of a novel SLC6A6 mutation in Leber congenital amaurosis |
| title_fullStr | Whole-exome sequencing and molecular dynamics confirm pathogenicity of a novel SLC6A6 mutation in Leber congenital amaurosis |
| title_full_unstemmed | Whole-exome sequencing and molecular dynamics confirm pathogenicity of a novel SLC6A6 mutation in Leber congenital amaurosis |
| title_short | Whole-exome sequencing and molecular dynamics confirm pathogenicity of a novel SLC6A6 mutation in Leber congenital amaurosis |
| title_sort | whole exome sequencing and molecular dynamics confirm pathogenicity of a novel slc6a6 mutation in leber congenital amaurosis |
| topic | Next-generation sequencing SLC6A6 Leber congenital amaurosis Whole-exome sequencing Homology modeling |
| url | https://doi.org/10.1186/s43042-025-00659-x |
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