Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements |
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Authors: | Feng Wang Hui Wang Han-Fang Tuan Duy H. Nguyen Vincent Sun Vafa Keser Sara J. Bowne Lori S. Sullivan Hongrong Luo Ling Zhao Xia Wang Jacques E. Zaneveld Jason S. Salvo Sorath Siddiqui Louise Mao Dianna K. Wheaton David G. Birch Kari E. Branham John R. Heckenlively Cindy Wen Ken Flagg Henry Ferreyra Jacqueline Pei Ayesha Khan Huanan Ren Keqing Wang Irma Lopez Raheel Qamar Juan C. Zenteno Raul Ayala-Ramirez Beatriz Buentello-Volante Qing Fu David A. Simpson Yumei Li Ruifang Sui Giuliana Silvestri Stephen P. Daiger Robert K. Koenekoop Kang Zhang Rui Chen |
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Affiliation: | 1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA 2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA 3. Institute for Genomic Medicine and Shiley Eye Center, University of California San Diego, La Jolla, CA, 92093, USA 4. McGill Ocular Genetics Laboratory, Division of Paediatric Ophthalmology, Departments of Human Genetics, Paediatric Surgery and Ophthalmology, McGill University Health Centre, Montreal, QC, H3H 1P3, Canada 5. Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, TX, 77030, USA 6. Molecular Medicine Research Center and Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China 7. Structural and Computational Biology and Molecular Biophysics Graduate Program, Houston, TX, 77030, USA 8. The Retina Foundation of the Southwest, Dallas, TX, 75231, USA 9. Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA 10. COMSATS Institute of Information Technology, Islamabad, 45600, Pakistan 11. Al-Nafees Medical College and Hospital, Isra University, Islamabad, 45600, Pakistan 12. Department of Genetics-Research Unit, Institute of Ophthalmology “Conde de Valenciana” and Biochemistry Department, Faculty of Medicine, UNAM, Mexico City, Mexico 13. Department of Ophthalmology, North Huashan Hospital, Fudan University, Shanghai, 200040, China 14. Centre for Vision and Vascular Science, Clinical ICS-A, Queen’s University Belfast, Grosvenor Road, Belfast, BT12 6BA, UK 15. Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, 100730, China 16. Department of Ophthalmology and Visual Science, The University of Texas Health Science Center, Houston, TX, 77030, USA 17. Veterans Administration Healthcare System, San Diego, CA, 92161, USA 18. The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA 19. Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA
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Abstract: | Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling. |
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