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. 2015 Feb 24;56(3):1937-46.
doi: 10.1167/iovs.14-16065.

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

Jason Salvo  1 , Vera Lyubasyuk  2 , Mingchu Xu  3 , Hui Wang  3 , Feng Wang  3 , Duy Nguyen  2 , Keqing Wang  4 , Hongrong Luo  2 , Cindy Wen  2 , Catherine Shi  2 , Danni Lin  2 , Kang Zhang  2 , Rui Chen  5
Affiliations

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

Jason Salvo et al. Invest Ophthalmol Vis Sci. .

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.

Keywords: FEVR; familial segregation; next-generation sequencing; novel alleles.

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Figures

Figure 1
Figure 1
Sequencing coverage achieved indicates high quality data. The solid line represents the percentage of targeted regions falling at or above the specified minimal coverage. The dashed lines represent the 95% confidence interval of this data.
Figure 2
Figure 2
Solved cases based on associated disease genes. Cases with mutations in LRP5 have been split into separate categories for dominant and recessive cases. “Multiple” indicates that potentially causative variants were found in more than one disease-associated gene.
Figure 3
Figure 3
Pedigree and mutation segregation of LRP5 mutation carried in family 1346.
Figure 4
Figure 4
Pedigree and mutation segregation of LRP5 mutation carried in family 1348.
Figure 5
Figure 5
Pedigree and mutation segregation of FZD4 mutation carried in family 1080.
Figure 6
Figure 6
Pedigree and mutation segregation of FZD4 mutation carried in family 1344.
Figure 7
Figure 7
Pedigree and mutation segregation of TSPAN12 mutation carried in family 0810.
Figure 8
Figure 8
Pedigree and mutation segregation of ZNF408 mutation carried by family 14022.
See this image and copyright information in PMC

References

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