Jason Salvo1, Vera Lyubasyuk2, Mingchu Xu3, Hui Wang3, Feng Wang3, Duy Nguyen2, Keqing Wang4, Hongrong Luo2, Cindy Wen2, Catherine Shi2, Danni Lin2, Kang Zhang2, Rui Chen5. 1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Structural and Computational Biology & Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, United States. 2. Department of Ophthalmology, Institute of Genomic Medicine, University of California, San Diego, San Diego, California, United States. 3. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States. 4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States. 5. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Structural and Computational Biology & Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States.
Abstract
PURPOSE: Familial exudative vitreoretinopathy (FEVR) is a developmental disease that can cause visual impairment and retinal detachment at a young age. Four genes involved in the Wnt signaling pathway were previously linked to this disease: NDP, FDZ4, LRP5, and TSPAN12. Identification of novel disease-causing alleles allows for a deeper understanding of the disease, better molecular diagnosis, and improved treatment. METHODS: Sequencing libraries from 92 FEVR patients were generated using a custom capture panel to enrich for 163 known retinal disease-causing genes in humans. Samples were processed using next generation sequencing (NGS) techniques followed by data analysis to identify and classify single nucleotide variants and small insertions and deletions. Sanger validation and segregation testing were used to verify suspected variants. RESULTS: Of the cohort of 92, 45 patients were potentially solved (48.9%). Solved cases resulted from the determination of 49 unique mutations, 41 of which are novel. Of the novel variants discovered, 13 were highly likely to cause FEVR due to the nature of these variants (frameshifting indels, splicing mutations, and nonsense variants types). To our knowledge, this is the largest study of a FEVR cohort using NGS. CONCLUSIONS: We were able to determine probable disease-causing variants in a large number of FEVR patients, the majority of which were novel. Knowledge of these variants will help to further characterize and diagnose FEVR. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.
PURPOSE:Familial exudative vitreoretinopathy (FEVR) is a developmental disease that can cause visual impairment and retinal detachment at a young age. Four genes involved in the Wnt signaling pathway were previously linked to this disease: NDP, FDZ4, LRP5, and TSPAN12. Identification of novel disease-causing alleles allows for a deeper understanding of the disease, better molecular diagnosis, and improved treatment. METHODS: Sequencing libraries from 92 FEVRpatients were generated using a custom capture panel to enrich for 163 known retinal disease-causing genes in humans. Samples were processed using next generation sequencing (NGS) techniques followed by data analysis to identify and classify single nucleotide variants and small insertions and deletions. Sanger validation and segregation testing were used to verify suspected variants. RESULTS: Of the cohort of 92, 45 patients were potentially solved (48.9%). Solved cases resulted from the determination of 49 unique mutations, 41 of which are novel. Of the novel variants discovered, 13 were highly likely to cause FEVR due to the nature of these variants (frameshifting indels, splicing mutations, and nonsense variants types). To our knowledge, this is the largest study of a FEVR cohort using NGS. CONCLUSIONS: We were able to determine probable disease-causing variants in a large number of FEVRpatients, the majority of which were novel. Knowledge of these variants will help to further characterize and diagnose FEVR. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.
Authors: Johane Robitaille; Marcia L E MacDonald; Ajamete Kaykas; Laird C Sheldahl; Jutta Zeisler; Marie-Pierre Dubé; Lin-Hua Zhang; Roshni R Singaraja; Duane L Guernsey; Binyou Zheng; Lee F Siebert; Ann Hoskin-Mott; Michael T Trese; Simon N Pimstone; Barkur S Shastry; Randall T Moon; Michael R Hayden; Y Paul Goldberg; Mark E Samuels Journal: Nat Genet Date: 2002-08-12 Impact factor: 38.330
Authors: Carmel Toomes; Helen M Bottomley; Sheila Scott; David A Mackey; Jamie E Craig; Binoy Appukuttan; J Timothy Stout; Christina J Flaxel; Kang Zhang; Graeme C M Black; Alan Fryer; Louise M Downey; Chris F Inglehearn Journal: Invest Ophthalmol Vis Sci Date: 2004-07 Impact factor: 4.799
Authors: Carmel Toomes; Helen M Bottomley; Richard M Jackson; Katherine V Towns; Sheila Scott; David A Mackey; Jamie E Craig; Li Jiang; Zhenglin Yang; Richard Trembath; Geoffrey Woodruff; Cheryl Y Gregory-Evans; Kevin Gregory-Evans; Michael J Parker; Graeme C M Black; Louise M Downey; Kang Zhang; Chris F Inglehearn Journal: Am J Hum Genet Date: 2004-03-11 Impact factor: 11.025
Authors: Evangelia S Panagiotou; Carla Sanjurjo Soriano; James A Poulter; Emma C Lord; Denisa Dzulova; Hiroyuki Kondo; Atsushi Hiyoshi; Brian Hon-Yin Chung; Yoyo Wing-Yiu Chu; Connie H Y Lai; Mark E Tafoya; Dyah Karjosukarso; Rob W J Collin; Joanne Topping; Louise M Downey; Manir Ali; Chris F Inglehearn; Carmel Toomes Journal: Am J Hum Genet Date: 2017-06-01 Impact factor: 11.025