Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients.

TitleNext-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients.
Publication TypeJournal Article
Year of Publication2015
AuthorsSalvo, J, Lyubasyuk, V, Xu, M, Wang, H, Wang, F, Nguyen, D, Wang, K, Luo, H, Wen, C, Shi, C, Lin, D, Zhang, K, Chen, R
JournalInvest Ophthalmol Vis Sci
Volume56
Issue3
Pagination1937-46
Date Published2015 Feb 24
ISSN1552-5783
KeywordsCohort Studies, DNA Mutational Analysis, DNA-Binding Proteins, Eye Proteins, Female, Frizzled Receptors, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Low Density Lipoprotein Receptor-Related Protein-5, Male, Mutation, Nerve Tissue Proteins, Retinal Diseases, Sequence Analysis, DNA, Tetraspanins, Transcription Factors
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.

DOI10.1167/iovs.14-16065
Alternate JournalInvest. Ophthalmol. Vis. Sci.
PubMed ID25711638
PubMed Central IDPMC4365990
Grant ListT32EY07102 / EY / NEI NIH HHS / United States
1S10RR026550 / RR / NCRR NIH HHS / United States
P30 EY022589 / EY / NEI NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
R01EY018571 / EY / NEI NIH HHS / United States
S10 RR026550 / RR / NCRR NIH HHS / United States
R01 EY022356 / EY / NEI NIH HHS / United States
P30EY022589 / EY / NEI NIH HHS / United States
TL1 TR000098 / TR / NCATS NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
TL1TR00098 / TR / NCATS NIH HHS / United States
R01EY022356 / EY / NEI NIH HHS / United States
T32 EY007102 / EY / NEI NIH HHS / United States