Cohort study of genotype and clinical phenotype in 34 families with familial exudative vitreoretinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Chen Chunli ¹ , Zhao Peiquan ² ,  Li Xiaorong ¹

1. Tianjin Medical University Eye Hospital, Tianjin Medical University Eye Institute, The College of Optometry & Ophthalmology, Tianjin 300384, China;
2. Department of Ophtalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200092, China;
Chen Chunli is working on the Department of Ophthalmology, Shengli Oilfield Central Hospital in Dongying City of Shandong Province, Dongying 257000, China;
Zhao Peiquan and Li Xiaorong are contributed equally to the article;

Corresponding author：

Li Xiaorong, Email: xiaorli@163.com

Keywords：

Retinal diseases/genetics; Genotype; Mutation; Familial exudative vitreoretinopathy

DOI：

10.3760/cma.j.cn511434-20190729-00240

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Objective To observe and analyze the genotype and clinical phenotype in 34 families of familial exudative vitreoretinopathy associated with (FEVR) gene variation.Methods Cohort study. Thirty-four FEVR families, in which the patients and both of their parents were all found to have FEVR-related gene mutations (proband 34 cases, 67 eyes; parents 68 cases, 136 eyes), were included in the study. These patients were identifIed from 722 FEVR patients through genetic screening, which diagnosed in Department of Ophtalmology of Xinhua Hospital and Tianjin Medical University Eye Hospital from January 2010 to December 2018. The probands and their parents underwent a comprehensive ophthalmological examination appropriate to their age, including BCVA, intraocular pressure, axial length, slit lamp examination, indirect ophthalmoscopy, FFA or color fundus photography or wide field color fundus photography. According to the severity of the disease, the clinical manifestations were divided into severe phenotype and mild phenotype. Thirty-four normal healthy people over 40 years old were included as the control group. The peripheral blood samples of FEVR family members and control group members were collected, and the genes known to be involved in FEVR, such as FZD4, LRP5, NDP, TSPAN12, ZNF408 and KIF11, were analyzed by next generation sequencing molecular genetics. The data were statistically analyzed by SPSS. The counting data was expressed in numbers or rates, and tested by Kruskal-Wallis test and χ² test to find out the existence of significant difference.Results In 67 eyes of the 34 probands, 48 eyes (71.64%) were classified into severe phenotype and 19 eyes (28.36%) were mild phenotype. In 136 eyes of 68 parents of the proband patients, 76 eyes (55.88%) were normal, 60 eyes (44.12%) were classified into mild phenotype, and no severe phenotype was found. A total of 65 variants of FEVR-related genes were detected in the 34 probands, of which LRP5 mutation was the most common (64.61%), followed by FZD4 (12.31%), NDP (10.77%), TSPAN12 (6.15%), ZNF408 (4.62%) and KIF11 (1.54%). Missense mutations were the most common variant in FEVR-related genes. However, the results of correlation analysis indicated that there was no significant correlation between the type of mutation and the severity of clinical phenotype (H=1.775, P=0.620). Among the 65 mutation types, 21 types have been previously identified and 44 were novel in this study. Thirty-nine eyes of 20 cases had only one single pathogenic mutation gene but with multiple mutation sites, 26 eyes of 13 cases carried 2 relevant pathogenic mutation genes, and 2 eyes in one case had 3 pathogenic mutation genes. The mutation frequencies of LRP5, NDP, ZNF408, FZD4, TSPAN12 and KIF11 genes in probands were significantly higher than those in control group, and the difference was statistically significant. The total mutation frequencies of LRP5, NDP, ZNF408, FZD4, TSPAN12 and KIF11 genes in proband group were significantly higher than those in control group (χ²=64.702, P＜0.001).Conclusions In the FEVR families, the most frequent mutations were those in LRP5, followed by FZD4, NDP, TSPAN12,ZNF408 and KIF11. Missense mutation is the most common type of FEVR-related gene mutation, but there is no significant correlation between the clinical phenotype and gene variation type. Most of the probands were with severe clinical phenotype, while most of the parents with FEVR pathogenic gene mutation showed normal or mild manifestations.

Citation： Chen Chunli, Zhao Peiquan, Li Xiaorong. Cohort study of genotype and clinical phenotype in 34 families with familial exudative vitreoretinopathy. Chinese Journal of Ocular Fundus Diseases, 2020, 36(3): 184-191. doi: 10.3760/cma.j.cn511434-20190729-00240 Copy

1.	Boonstra FN, van Nouhuys CE, Schuil J, et al. Clinical and molecular evaluation of probands and family members with familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2009, 50(9): 4379-4385. DOI: 10.1167/iovs.08-3320.
2.	Nikopoulos K, Gilissen C, Hoischen A, et al. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy[J]. Am J Hum Genet, 2010, 86(2): 240-247. DOI: 10.1016/j.ajhg.2009.12.016.
3.	Robitaille J, Macdonald ML, Kaykas A, et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy[J]. Nat Genet, 2002, 32(2): 326-330. DOI: 10.1038/ng957.
4.	Dickinson JL, Sale MM, Passmore A, et al. Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity[J]. Clin Exp Ophthalmol, 2006, 34(7): 682-688. DOI: 10.1111/j.1442-9071.2006.01314.x.
5.	Musada GR, Syed H, Jalali S, et al. Mutation spectrum of the FZD-4, TSPAN12 and ZNF408 genes in Indian FEVR patients[J/OL]. BMC Ophthalmol, 2016, 16: 90[2016-06-17]. https://link.springer.com/article/10.1186/s12886-016-0236-y. DOI: 10.1186/s12886-016-0236-y.
6.	Seo SH, Yu YS, Park SW, et al. Molecular characterization of FZD4, LRP5, and TSPAN12 in familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2015, 56(9): 5143-5151. DOI: 10.1167/iovs.14-15680.
7.	Rao FQ, Cai XB, Cheng FF, et al. Mutations in LRP5, FZD4, TSPAN12, NDP, ZNF408, or KIF11 genes account for 38.7% of Chinese patients with familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(5): 2623-2629.
8.	Li JK, Fei P, Li Y, et al. Identification of novel KIF11 mutations in patients with familial exudative vitreoretinopathy and a phenotypic analysis[J/OL]. Sci Rep, 2016, 6: 26564[2016-05-23]. http://dx.doi.org/10.1038/srep26564. DOI: 10.1167/iovs.14-15680.
9.	Li Y, Peng J, Li J, et al. The characteristics of digenic familial exudative vitreoretinopathy[J]. Graefe’s Arch Clin Exp Ophthalmol, 2018, 256(11): 2149-2156. DOI: 10.1007/s00417-018-4076-8.
10.	Li JK, Li Y, Zhang X, et al. Spectrum of variants in 389 Chinese probands with familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2018, 59(13): 5368-5381. DOI: 10.1167/iovs.17-23541.
11.	Pendergast SD, Trese MT. Familial exudative vitreoretinopathy: results of surgical management[J]. Ophthalmology, 1998, 105(6): 1015-1023. DOI: 10.1016/S0161-6420(98)96002-X.
12.	Richards S, Aziz N, Bale S, et al. 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[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
13.	Qin M, Hayashi H, OshimaK, et al. Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes[J]. Hum Mutat, 2005, 26(2): 104-112. DOI: 10.1002/humu.20191.
14.	Stiegel E, Say EA, Carter BC, et al. Simultaneous FZD4 and LRP5 mutation in autosomal dominant familial exudative vitreoretinopathy[J]. Retin Cases Brief Rep, 2013, 7(1): 26-28. DOI: 10.1097/ICB.0b013e31827537eb.
15.	Salvo J, Lyubasyuk V, Xu M, et al. Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients[J]. Invest Ophthalmol Vis Sci, 2015, 56(3): 1937-1946. DOI: 10.1167/iovs.14-16065.
16.	Kramer GD, Say EA, Shields CL. Simultaneous novel mutations of LRP5 and TSPAN12 in a case of familial exudative vitreoretinopathy[J/OL]. J Pediatr Ophthalmol Strabismus, 2016, 53: 1-5[2016-02-04]. https://www.healio.com/ophthalmology/journals/jpos/%7Bf68833fc-707b-4b6a-aace-27893cc54d71%7D/simultaneous-novel-mutations-of-lrp5-and-tspan12-in-a-case-of-familial-exudative-vitreoretinopathy. DOI: 10.3928/01913913-20151215-01.
17.	Schatz P, Khan AO. Variable familial exudative vitreoretinopathy in a family harbouring variants in both FZD4 and TSNPAN12[J]. Acta Ophthalmol, 2017, 95(7): 705-709. DOI: 10.1111/aos.13411.
18.	Muller M, Kusserow C, Orth U, et al. Mutations of the frizzled-4 gene. Their impact on medical care of patients with autosomal dominant exudative vitreoretinopathy[J]. Ophthalmologe, 2008, 105(3): 262-268. DOI: 10.1007/s00347-007-1617-7.
19.	Nikopoulos K, Venselaar H, Collin RW, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP[J]. Hum Mutat, 2010, 31(6): 656-666. DOI: 10.1002/humu.21250.
20.	Hiraoka M, Takahashi H, Orimo H, et al. Genetic screening of Wnt signaling factors in advanced retinopathy of prematurity[J]. Mol Vis, 2010, 16: 2572-2574. DOI: 10.1016/j.cbi.2010.08.006.
21.	Kondo H, Kusaka S, Yoshinaga A, et al. Mutations in the TSPAN12 gene in Japanese patients with familial exudative vitreoretinopathy[J]. Am J Ophthalmol, 2011, 151(6): 1095-1100. DOI: 10.1016/j.ajo.2010.11.026.
22.	Toomes C, Bottomley HM, Scott S, et al. Spectrum and frequency of FZD4 mutations in familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2004, 45(7): 2083-2090. DOI: 10.1167/iovs.03-1044.
23.	Fei P, Zhang Q, Huang L, et al. Identification of two novel LRP5 mutations in families with familial exudative vitreoretinopathy[J]. Mol Vis, 2014, 20: 395-409. DOI: 10.1002/sim.6031.

1. Boonstra FN, van Nouhuys CE, Schuil J, et al. Clinical and molecular evaluation of probands and family members with familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2009, 50(9): 4379-4385. DOI: 10.1167/iovs.08-3320.
2. Nikopoulos K, Gilissen C, Hoischen A, et al. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy[J]. Am J Hum Genet, 2010, 86(2): 240-247. DOI: 10.1016/j.ajhg.2009.12.016.
3. Robitaille J, Macdonald ML, Kaykas A, et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy[J]. Nat Genet, 2002, 32(2): 326-330. DOI: 10.1038/ng957.
4. Dickinson JL, Sale MM, Passmore A, et al. Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity[J]. Clin Exp Ophthalmol, 2006, 34(7): 682-688. DOI: 10.1111/j.1442-9071.2006.01314.x.
5. Musada GR, Syed H, Jalali S, et al. Mutation spectrum of the FZD-4, TSPAN12 and ZNF408 genes in Indian FEVR patients[J/OL]. BMC Ophthalmol, 2016, 16: 90[2016-06-17]. https://link.springer.com/article/10.1186/s12886-016-0236-y. DOI: 10.1186/s12886-016-0236-y.
6. Seo SH, Yu YS, Park SW, et al. Molecular characterization of FZD4, LRP5, and TSPAN12 in familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2015, 56(9): 5143-5151. DOI: 10.1167/iovs.14-15680.
7. Rao FQ, Cai XB, Cheng FF, et al. Mutations in LRP5, FZD4, TSPAN12, NDP, ZNF408, or KIF11 genes account for 38.7% of Chinese patients with familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(5): 2623-2629.
8. Li JK, Fei P, Li Y, et al. Identification of novel KIF11 mutations in patients with familial exudative vitreoretinopathy and a phenotypic analysis[J/OL]. Sci Rep, 2016, 6: 26564[2016-05-23]. http://dx.doi.org/10.1038/srep26564. DOI: 10.1167/iovs.14-15680.
9. Li Y, Peng J, Li J, et al. The characteristics of digenic familial exudative vitreoretinopathy[J]. Graefe’s Arch Clin Exp Ophthalmol, 2018, 256(11): 2149-2156. DOI: 10.1007/s00417-018-4076-8.
10. Li JK, Li Y, Zhang X, et al. Spectrum of variants in 389 Chinese probands with familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2018, 59(13): 5368-5381. DOI: 10.1167/iovs.17-23541.
11. Pendergast SD, Trese MT. Familial exudative vitreoretinopathy: results of surgical management[J]. Ophthalmology, 1998, 105(6): 1015-1023. DOI: 10.1016/S0161-6420(98)96002-X.
12. Richards S, Aziz N, Bale S, et al. 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[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
13. Qin M, Hayashi H, OshimaK, et al. Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes[J]. Hum Mutat, 2005, 26(2): 104-112. DOI: 10.1002/humu.20191.
14. Stiegel E, Say EA, Carter BC, et al. Simultaneous FZD4 and LRP5 mutation in autosomal dominant familial exudative vitreoretinopathy[J]. Retin Cases Brief Rep, 2013, 7(1): 26-28. DOI: 10.1097/ICB.0b013e31827537eb.
15. Salvo J, Lyubasyuk V, Xu M, et al. Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients[J]. Invest Ophthalmol Vis Sci, 2015, 56(3): 1937-1946. DOI: 10.1167/iovs.14-16065.
16. Kramer GD, Say EA, Shields CL. Simultaneous novel mutations of LRP5 and TSPAN12 in a case of familial exudative vitreoretinopathy[J/OL]. J Pediatr Ophthalmol Strabismus, 2016, 53: 1-5[2016-02-04]. https://www.healio.com/ophthalmology/journals/jpos/%7Bf68833fc-707b-4b6a-aace-27893cc54d71%7D/simultaneous-novel-mutations-of-lrp5-and-tspan12-in-a-case-of-familial-exudative-vitreoretinopathy. DOI: 10.3928/01913913-20151215-01.
17. Schatz P, Khan AO. Variable familial exudative vitreoretinopathy in a family harbouring variants in both FZD4 and TSNPAN12[J]. Acta Ophthalmol, 2017, 95(7): 705-709. DOI: 10.1111/aos.13411.
18. Muller M, Kusserow C, Orth U, et al. Mutations of the frizzled-4 gene. Their impact on medical care of patients with autosomal dominant exudative vitreoretinopathy[J]. Ophthalmologe, 2008, 105(3): 262-268. DOI: 10.1007/s00347-007-1617-7.
19. Nikopoulos K, Venselaar H, Collin RW, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP[J]. Hum Mutat, 2010, 31(6): 656-666. DOI: 10.1002/humu.21250.
20. Hiraoka M, Takahashi H, Orimo H, et al. Genetic screening of Wnt signaling factors in advanced retinopathy of prematurity[J]. Mol Vis, 2010, 16: 2572-2574. DOI: 10.1016/j.cbi.2010.08.006.
21. Kondo H, Kusaka S, Yoshinaga A, et al. Mutations in the TSPAN12 gene in Japanese patients with familial exudative vitreoretinopathy[J]. Am J Ophthalmol, 2011, 151(6): 1095-1100. DOI: 10.1016/j.ajo.2010.11.026.
22. Toomes C, Bottomley HM, Scott S, et al. Spectrum and frequency of FZD4 mutations in familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2004, 45(7): 2083-2090. DOI: 10.1167/iovs.03-1044.
23. Fei P, Zhang Q, Huang L, et al. Identification of two novel LRP5 mutations in families with familial exudative vitreoretinopathy[J]. Mol Vis, 2014, 20: 395-409. DOI: 10.1002/sim.6031.

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Cohort study of genotype and clinical phenotype in 34 families with familial exudative vitreoretinopathy

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