title: Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Jason
authors.initials: J
authors.lastname: Salvo
authors.affiliation: Department of Ophthalmology, Institute of Genomic Medicine, University of California, San Diego, San Diego, California, United States.
authors.forename: Vera
authors.initials: V
authors.lastname: Lyubasyuk
authors.affiliation: 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.
authors.forename: Mingchu
authors.initials: M
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Institute of Genomic Medicine, University of California, San Diego, San Diego, California, United States.
authors.forename: Duy
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Institute of Genomic Medicine, University of California, San Diego, San Diego, California, United States.
authors.forename: Hongrong
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Ophthalmology, Institute of Genomic Medicine, University of California, San Diego, San Diego, California, United States.
authors.forename: Cindy
authors.initials: C
authors.lastname: Wen
authors.affiliation: Department of Ophthalmology, Institute of Genomic Medicine, University of California, San Diego, San Diego, California, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Ophthalmology, Institute of Genomic Medicine, University of California, San Diego, San Diego, California, United States.
authors.forename: Danni
authors.initials: D
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology, Institute of Genomic Medicine, University of California, San Diego, San Diego, California, United States.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
mesh_terms: D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods*; D004268:DNA-Binding Proteins / Q000235:genetics; D015785:Eye Diseases, Hereditary; D005136:Eye Proteins / Q000235:genetics; D000080345:Familial Exudative Vitreoretinopathies; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D012164:Retinal Diseases / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D059470:Tetraspanins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D005136:Eye Proteins; C402930:FZD4 protein, human; D051157:Frizzled Receptors; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C081848:NDP protein, human; D009419:Nerve Tissue Proteins; D059470:Tetraspanins; D014157:Transcription Factors; C582974:ZNF408 protein, human
keywords: FEVR; familial segregation; next-generation sequencing; novel alleles