The characteristics of digenic familial exudative vitreoretinopathy
To describe and analyse the clinical and genetic characteristics of digenic familial exudative vitreoretinopathy (FEVR).
The study cohort consisted of patients with FEVR (n = 13) to identify patients with two mutations in two different genes. A genetic analysis of the LRP5, FZD4, TSPAN12, and ZNF408 genes was performed with next-generation sequencing (NGS). The genotype data obtained from the patients with FEVR were analysed and correlated with their clinical manifestations. They were then further evaluated in conjunction with other data that were available for these genes. The probands and parents/relatives underwent comprehensive age-appropriate ophthalmic examinations.
The medical history and genetic reports of 487 patients with FEVR were reviewed. In all, we identified 13 probands (2.67%, 13/487) with simultaneous mutations in two disease-causing genes. A total of 25 of mutations were found, including10 in FZD4, 8 in LRP5, 3 in ZNF408, 2 in NDP, and 2 in TSPAN12. The most frequent mutations were those in FZD4 and LRP5. We identified 8 mutations that had previously been identified and 17 novel variants. Among 26 eyes, 65.38% exhibited a phenotype, and 10 (38.46%) were stage 4, while 7 (26.92%) were stage 5.
This is the first study to report a group of patients with digenic FEVR. In most affected eyes, the stage was more severe than stage 3. We speculate that the phenotype of FEVR is more severe in patients with digenic rather than monogenic variants of FEVR-related genes.
KeywordsFEVR Gene Digenic FEVR Phenotype
This research was supported by the National Natural Science Foundation Project of China (81770964, 15XD1502800).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.
Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.
- 2.Boonstra FN, van Nouhuys CE, Schuil J, de Wijs IJ, van der Donk KP, Nikopoulos K, Mukhopadhyay A, Scheffer H, Tilanus MA, Cremers FP, Hoefsloot LH (2009) Clinical and molecular evaluation of probands and family members with familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci 50:4379–4385. https://doi.org/10.1167/iovs.08-3320 CrossRefPubMedGoogle Scholar
- 7.Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Toomes C, Downey L (1993) Familial exudative vitreoretinopathy, autosomal dominant. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, Amemiya A (eds) GeneReviews((R)). University of Washington, SeattleGoogle Scholar
- 15.Salvo 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 (2015) Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients. Invest Ophthalmol Vis Sci 56:1937–1946. https://doi.org/10.1167/iovs.14-16065 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Nikopoulos K, Venselaar H, Collin RW, Riveiro-Alvarez R, Boonstra FN, Hooymans JM, Mukhopadhyay A, Shears D, van Bers M, de Wijs IJ, van Essen AJ, Sijmons RH, Tilanus MA, van Nouhuys CE, Ayuso C, Hoefsloot LH, Cremers FP (2010) Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Hum Mutat 31:656–666. https://doi.org/10.1002/humu.21250 CrossRefPubMedGoogle Scholar
- 21.Collin RW, Nikopoulos K, Dona M, Gilissen C, Hoischen A, Boonstra FN, Poulter JA, Kondo H, Berger W, Toomes C, Tahira T, Mohn LR, Blokland EA, Hetterschijt L, Ali M, Groothuismink JM, Duijkers L, Inglehearn CF, Sollfrank L, Strom TM, Uchio E, van Nouhuys CE, Kremer H, Veltman JA, van Wijk E, Cremers FP (2013) ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature. Proc Natl Acad Sci U S A 110:9856–9861. https://doi.org/10.1073/pnas.1220864110 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Iarossi G, Bertelli M, Maltese PE, Gusson E, Marchini G, Bruson A, Benedetti S, Volpetti S, Catena G, Buzzonetti L, Ziccardi L (2017) Genotype-phenotype characterization of novel variants in six Italian patients with familial exudative vitreoretinopathy. J Ophthalmol 2017:3080245. https://doi.org/10.1155/2017/3080245 PubMedPubMedCentralCrossRefGoogle Scholar