Comprehensive analysis of pathogenic genes and clinical phenotypes in patients with Leber congenital amuarosis_Chinese Journal of Ocular Fundus Diseases

Authors：

Xing Dongjun , Li Zhiqing , Yu Rongguo , Wang Linni , Hu Liying , Yang Yang , Li Chang ,  Li Xiaorong

Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China;

Corresponding author：

Li Xiaorong, Email: xiaorli@163.com

Keywords：

Leber congenital amaurosis; Genes; Mutation; GUCY2D gene; CRB1 gene

DOI：

10.3760/cma.j.cn511434-20211116-00643

Video：

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Objective To observe clinical phenotypes and analyze the pathogenic genes of Leber congenital amaurosis (LCA). Methods A retrospective clinical study. From 2019 to 2020, 2 patients diagnosed with LCA by genetic testing in Tianjin Medical University Eye Hospital and their 6 unaffected family members were enrolled in the study. Two patients were from 2 unrelated families, both were probands. The patient's medical history was inquired in detail, slit lamp microscopy, ultra-widefield fundus photography, autofluorescence, and flash visual evoked potential (F-VEP) were performed. Peripheral vein blood (3-5 ml) was collected and genomic DNA was extracted from all study subjects. A total of 381 pathogetic genes associated with inherited retinal diseases, were selected by targeted exome sequencing capture strategy. Sanger sequencing was used to verify suspected pathogenic mutations. Candidate pathogenic mutations were identified after bioinformatics analysis. Sanger sequencing, real-time quantitative polymerase chain reaction and family co-identification were used to confirm the final mutations. Results Two patients were male, aged 3 and 27 years. One case had vision loss in both eyes, accompanied by nystagmus and acupressure eye sign since childhood. The clinical hallmark of the proband (F1-Ⅱ-3) in F1 includes clearly boundary of optic disc, normal retinal blood vessels and macular fovea. The implied period of the maximum forward wave in both eyes of F-VEP was roughly normal, and its amplitude decreased significantly. The phenotype of the proband (F2-Ⅱ-1) in F2 includes optic nerve head pallor, bone-spicule intraretinal pigmentation, “gold-foil maculopathy”, retina patchy hypo-autofluorescence in both eyes. There was no abnormal phenotype in the eyes of the family members. According to the genetic diagnosis, the proband (F1-Ⅱ-3) carried the GUCY2D gene c.835G>A (p.D279N) (M1) and exon 9-19 deletion (M2) compound heterozygous mutations, in which M1 was derived from healthy mother and M2 was derived from healthy father. The proband (F2-Ⅱ-1) carried CRB1 gene c.1576C>T(R526X) (M3) and c.1522T>C (C508R) (M4) compound heterozygous mutations, in which M3 from the healthy father, M4 from the healthy mother. M2 and M4 were novel mutations. Conclusion GUCY2D gene mutations lead to LCA1 type in the F1 family, CRB1 gene mutations lead to LCA8 type in the F2 family; there are significant different phenotypes caused by different pathogenic genes.

Citation： Xing Dongjun, Li Zhiqing, Yu Rongguo, Wang Linni, Hu Liying, Yang Yang, Li Chang, Li Xiaorong. Comprehensive analysis of pathogenic genes and clinical phenotypes in patients with Leber congenital amuarosis. Chinese Journal of Ocular Fundus Diseases, 2022, 38(8): 663-667. doi: 10.3760/cma.j.cn511434-20211116-00643 Copy

1.	Kumaran N, Moore AT, Weleber RG, et al. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions[J]. Br J Ophthalmol, 2017, 101(9): 1147-1154. DOI: 10.1136/bjophthalmol-2016-309975.
2.	Viswarubhiny S, Anjanamurthy R, Vanniarajan A, et al. Clinical exome sequencing facilitates the understanding of genetic heterogeneity in Leber congenital amaurosis patients with variable phenotype in Southern India[J]. Eye Vis (Lond), 2021, 8(1): 20. DOI: 10.1186/s40662-021-00243-5.
3.	Li L, Xiao X, Li S, et al. Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis[J/OL]. PLoS One, 2011, 6(5): e19458[2011-05-13]. https://pubmed.ncbi.nlm.nih.gov/21602930/. DOI: 10.1371/journal.pone.0019458.
4.	Chen Y, Zhang Q, Shen T, et al. Comprehensive mutation analysis by whole-exome sequencing in 41 Chinese families with Leber congenital amaurosis[J]. Invest Ophthalmol Vis Sci, 2013, 54(6): 4351-4357. DOI: 10.1167/iovs.13-11606.
5.	Boye SE. Leber congenital amaurosis caused by mutations in GUCY2D[J/OL]. Cold Spring Harb Perspect Med, 2014, 5(1): a17350[2014-09-25]. https://pubmed.ncbi.nlm.nih.gov/25256176/. DOI: 10.1101/cshperspect.a017350.
6.	王诗园, 张翔, 彭婕, 等. CRB1突变型Leber先天性黑矇和早发视网膜萎缩患儿基因型与表型特征研究[J]. 中华眼底病杂志, 2021, 37(4): 284-289. DOI: 10.3760/cma.j.cn511434-20200929-00478.Wang SY, Zhang X, Peng J, et al. Genotype and phenotype of CRB1 mutated Leber congenital amaurosis and early-onset retinal atrophy[J]. Chin J Ocul Fundus Dis, 2021, 37(4): 284-289. DOI: 10.3760/cma.j.cn511434-20200929-00478.
7.	Wang H, Wang X, Zou X, et al. Comprehensive molecular diagnosis of a large Chinese Leber congenital amaurosis cohort[J]. Invest Ophthalmol Vis Sci, 2015, 56(6): 3642-3655. DOI: 10.1167/iovs.14-15972.
8.	Chen X, Zhao K, Sheng X, et al. Targeted sequencing of 179 genes associated with hereditary retinal dystrophies and 10 candidate genes identifies novel and known mutations in patients with various retinal diseases[J]. Invest Ophthalmol Vis Sci, 2013, 54(3): 2186-2197. DOI: 10.1167/iovs.12-10967.
9.	Milam AH, Barakat MR, Gupta N, et al. Clinicopathologic effects of mutant GUCY2D in Leber congenital amaurosis[J]. Ophthalmology, 2003, 110(3): 549-558. DOI: 10.1016/S0161-6420(02)01757-8.
10.	Sharon D, Wimberg H, Kinarty Y, et al. Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D[J]. Prog Retin Eye Res, 2018, 63: 69-91. DOI: 10.1016/j.preteyeres.2017.10.003.
11.	Peshenko IV, Olshevskaya EV, Dizhoor AM. Evaluating the role of retinal membrane guanylyl cyclase 1 (RetGC1) domains in binding guanylyl cyclase-activating proteins (GCAPs)[J]. J Biol Chem, 2015, 290(11): 6913-6924. DOI: 10.1074/jbc.M114.629642.
12.	Winger JA, Derbyshire ER, Lamers MH, et al. The crystal structure of the catalytic domain of a eukaryotic guanylate cyclase[J]. BMC Struct Biol, 2008, 8: 42. DOI: 10.1186/1472-6807-8-42.
13.	Berman HM, Westbrook J, Feng Z, et al. The protein data bank[J]. Nucleic Acids Res, 2000, 28(1): 235-242. DOI: 10.1107/s0907444902003451.
14.	Richard M, Roepman R, Aartsen WM, et al. Towards understanding CRUMBS function in retinal dystrophies[J]. Hum Mol Genet, 2006, 15: 235-243. DOI: 10.1093/hmg/ddl195.
15.	Pocha SM, Knust E. Complexities of Crumbs function and regulation in tissue morphogenesis[J]. Curr Biol, 2013, 23(7): 289-293. DOI: 10.1016/j.cub.2013.03.001.
16.	Stenson PD, Ball EV, Mort M, et al. Human Gene Mutation Database (HGMD): 2003 update[J]. Hum Mutat, 2003, 21(6): 577-581. DOI: 10.1002/humu.10212.
17.	Beryozkin A, Zelinger L, Bandah-Rozenfeld D, et al. Mutations in CRB1 are a relatively common cause of autosomal recessive early-onset retinal degeneration in the Israeli and Palestinian populations[J]. Invest Ophthalmol Vis Sci, 2013, 54(3): 2068-2075. DOI: 10.1167/iovs.12-11419.
18.	王诗园, 赵培泉. Leber先天性黑矇分子遗传研究进展[J]. 中国实用眼科杂志, 2017, 35(7): 663-667. DOI: 10.3760/cma.j.issn.1006-4443.2017.07.002.Wang SY, Zhao PQ. Advances in molecular genetics of Leber congenital amaurosis[J]. Chin J Pract Ophthalmol, 2017, 35(7): 663-667. DOI: 10.3760/cma.j.issn.1006-4443.2017.07.002.

1. Kumaran N, Moore AT, Weleber RG, et al. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions[J]. Br J Ophthalmol, 2017, 101(9): 1147-1154. DOI: 10.1136/bjophthalmol-2016-309975.
2. Viswarubhiny S, Anjanamurthy R, Vanniarajan A, et al. Clinical exome sequencing facilitates the understanding of genetic heterogeneity in Leber congenital amaurosis patients with variable phenotype in Southern India[J]. Eye Vis (Lond), 2021, 8(1): 20. DOI: 10.1186/s40662-021-00243-5.
3. Li L, Xiao X, Li S, et al. Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis[J/OL]. PLoS One, 2011, 6(5): e19458[2011-05-13]. https://pubmed.ncbi.nlm.nih.gov/21602930/. DOI: 10.1371/journal.pone.0019458.
4. Chen Y, Zhang Q, Shen T, et al. Comprehensive mutation analysis by whole-exome sequencing in 41 Chinese families with Leber congenital amaurosis[J]. Invest Ophthalmol Vis Sci, 2013, 54(6): 4351-4357. DOI: 10.1167/iovs.13-11606.
5. Boye SE. Leber congenital amaurosis caused by mutations in GUCY2D[J/OL]. Cold Spring Harb Perspect Med, 2014, 5(1): a17350[2014-09-25]. https://pubmed.ncbi.nlm.nih.gov/25256176/. DOI: 10.1101/cshperspect.a017350.
6. 王诗园, 张翔, 彭婕, 等. CRB1突变型Leber先天性黑矇和早发视网膜萎缩患儿基因型与表型特征研究[J]. 中华眼底病杂志, 2021, 37(4): 284-289. DOI: 10.3760/cma.j.cn511434-20200929-00478.Wang SY, Zhang X, Peng J, et al. Genotype and phenotype of CRB1 mutated Leber congenital amaurosis and early-onset retinal atrophy[J]. Chin J Ocul Fundus Dis, 2021, 37(4): 284-289. DOI: 10.3760/cma.j.cn511434-20200929-00478.
7. Wang H, Wang X, Zou X, et al. Comprehensive molecular diagnosis of a large Chinese Leber congenital amaurosis cohort[J]. Invest Ophthalmol Vis Sci, 2015, 56(6): 3642-3655. DOI: 10.1167/iovs.14-15972.
8. Chen X, Zhao K, Sheng X, et al. Targeted sequencing of 179 genes associated with hereditary retinal dystrophies and 10 candidate genes identifies novel and known mutations in patients with various retinal diseases[J]. Invest Ophthalmol Vis Sci, 2013, 54(3): 2186-2197. DOI: 10.1167/iovs.12-10967.
9. Milam AH, Barakat MR, Gupta N, et al. Clinicopathologic effects of mutant GUCY2D in Leber congenital amaurosis[J]. Ophthalmology, 2003, 110(3): 549-558. DOI: 10.1016/S0161-6420(02)01757-8.
10. Sharon D, Wimberg H, Kinarty Y, et al. Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D[J]. Prog Retin Eye Res, 2018, 63: 69-91. DOI: 10.1016/j.preteyeres.2017.10.003.
11. Peshenko IV, Olshevskaya EV, Dizhoor AM. Evaluating the role of retinal membrane guanylyl cyclase 1 (RetGC1) domains in binding guanylyl cyclase-activating proteins (GCAPs)[J]. J Biol Chem, 2015, 290(11): 6913-6924. DOI: 10.1074/jbc.M114.629642.
12. Winger JA, Derbyshire ER, Lamers MH, et al. The crystal structure of the catalytic domain of a eukaryotic guanylate cyclase[J]. BMC Struct Biol, 2008, 8: 42. DOI: 10.1186/1472-6807-8-42.
13. Berman HM, Westbrook J, Feng Z, et al. The protein data bank[J]. Nucleic Acids Res, 2000, 28(1): 235-242. DOI: 10.1107/s0907444902003451.
14. Richard M, Roepman R, Aartsen WM, et al. Towards understanding CRUMBS function in retinal dystrophies[J]. Hum Mol Genet, 2006, 15: 235-243. DOI: 10.1093/hmg/ddl195.
15. Pocha SM, Knust E. Complexities of Crumbs function and regulation in tissue morphogenesis[J]. Curr Biol, 2013, 23(7): 289-293. DOI: 10.1016/j.cub.2013.03.001.
16. Stenson PD, Ball EV, Mort M, et al. Human Gene Mutation Database (HGMD): 2003 update[J]. Hum Mutat, 2003, 21(6): 577-581. DOI: 10.1002/humu.10212.
17. Beryozkin A, Zelinger L, Bandah-Rozenfeld D, et al. Mutations in CRB1 are a relatively common cause of autosomal recessive early-onset retinal degeneration in the Israeli and Palestinian populations[J]. Invest Ophthalmol Vis Sci, 2013, 54(3): 2068-2075. DOI: 10.1167/iovs.12-11419.
18. 王诗园, 赵培泉. Leber先天性黑矇分子遗传研究进展[J]. 中国实用眼科杂志, 2017, 35(7): 663-667. DOI: 10.3760/cma.j.issn.1006-4443.2017.07.002.Wang SY, Zhao PQ. Advances in molecular genetics of Leber congenital amaurosis[J]. Chin J Pract Ophthalmol, 2017, 35(7): 663-667. DOI: 10.3760/cma.j.issn.1006-4443.2017.07.002.

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Comprehensive analysis of pathogenic genes and clinical phenotypes in patients with Leber congenital amuarosis

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