Clinical manifestations and genetic analysis of six different families of Leber's congenital amaurosis_Chinese Journal of Ocular Fundus Diseases

Authors：

Bai Zhouxian ¹ , Shao Jingzhi ² , Chen Yibing ¹ ,  Kong Xiangdong ¹

1. The Genetic and Prenatal Diagnosis Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China;
2. Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China;

Corresponding author：

Kong Xiangdong, Email: kongxd@263.net

Keywords：

Leber congenital amaurosis/etiology; Genes; Mutation; TULP1 gene; RPGRIP1 gene; GUCY2D gene

DOI：

10.3760/cma.j.cn511434-20200430-00191

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Objective To observe and analyze the pathogenic gene types and clinical phenotypes of Leber congenital amaurosis (LCA).Methods A retrospective clinical study. Six patients with LCA confirmed by genetic testing and 18 family members were included in the study. The patients came from six unrelated families. The family was investigated with a specific hereditary eye disease enrichment panel which contained 463 known pathogenic genes and based on targeted exome capture technology first to indentify the potential pathogenic genes and mutations. Then the TULP1, RPGRIP1, GUCY2D pathogenic mutations were conformed by Sanger sequencing. The pathogenicity of the gene variation was searched through relevant databases and PubMed literature, and its function was explained by protein prediction software.Results Of the 6 patients, 3 were males and 3 were females; the age was from 3 to 33 years. Nystagmus, finger pressing eyes, photophobia, and night blindness were seen in 5 cases; electroretinogram showed 3 cases of extinction or near extinction; and 4 cases of retinopathy. The results showed patients with compound heterozygous mutation of c.1318C＞T and c.1142T＞G, homozygous mutation ofc.1318C＞T and compound heterozygous mutation of c.1153G＞A and c.1561C＞T of TULP1 in Family 1, Family 2 and Family 5, respectively. There were compound heterozygous mutations of RPGRIP1 c.391delG and c.1468-2A＞G in Family 3 and c.715delA and c.1765C＞T in Family 6, respectively. Homozygous mutation of c.3177_3178delAC of GUCY2D was found in Family 4.The parents of all six patients were carriers of corresponding heterozygous mutations.TULP1 gene c.1142T＞G, RPGRIP1 gene c.391delG, c.715delA and c.1765C＞T and GUCY2D gene c.3177_3178delAC mutations were novel mutations and unreported. The 381th amino acid locus of product protein of TULP1 gene was highly conserved among species. The protein prediction software predicted that the mutation pathogenic. The c.391delG, c.715delA and c.1765C＞T mutations of RPGRIP1 gene and c.3177_3178delAC mutation of GUCY2D gene can lead to early translation termination of their product proteins, which are pathogenic variants.Conclusion The pathogenic mutations of TULP1, RPGRIP1 and GUCY2D genes led to LCA 15, LCA 6 and LCA 1 in six families.

Citation： Bai Zhouxian, Shao Jingzhi, Chen Yibing, Kong Xiangdong. Clinical manifestations and genetic analysis of six different families of Leber's congenital amaurosis. Chinese Journal of Ocular Fundus Diseases, 2021, 37(3): 195-200. doi: 10.3760/cma.j.cn511434-20200430-00191 Copy

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13.	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.
14.	王淑然. Leber先天性黑矇致病基因及相关临床表型研究进展[J]. 中华实验眼科杂志, 2013, 31(12): 1178-1182. DOI: 10.3760/cma.j.issn.2095-0160.2013.12.018.Wang SR. Current advance in genetics and clinical phenotype of Leber congenital amaurosis[J]. Chin J Exp Ophthalmol, 2013, 31(12): 1178-1182. DOI: 10.3760/cma.j.issn.2095-0160.2013.12.018.
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1. Zhang SQ, Jiang T, Li M, et al. Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis[J]. Nat Genet, 2012, 44(10): 1156-1160. DOI: 10.1038/ng.2409.
2. Wang P, Guo X, Zhang Q. Further evidence of autosomal-dominant Leber congenital amaurosis caused by heterozygous CRX mutation[J]. Graefe's Arch Clin Exp Ophthalmol, 2007, 245(9): 1401-1402. DOI: 10.1007/s00417-007-0554-0.
3. den Hollander AI, Roepman R, Koenekoop RK, et al. Leber congenital amaurosis: genes, proteins and disease mechanisms[J]. Prog Retin Eye Res, 2008, 27(4): 391-419. DOI: 10.1016/j.preteyeres.2008.05.003.
4. Schlessinger A, Yachdav G, Rost B. PROFbval: predict flexible and rigid residues in proteins[J]. Bioinformatics, 2006, 22(7): 891-893. DOI: 10.1093/bioinformatics/btl032.
5. 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.
6. 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://doi.org/10.1371/journal.pone.0019458. DOI: 10.1371/journal.pone.0019458.
7. Ullah I, Kabir F, Iqbal M, et al. Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases[J]. Mol Vis, 2016, 22: 797-815.
8. Kondo H, Qin M, Mizota A, et al. A homozygosity-based search for mutations in patients with autosomal recessive retinitis pigmentosa, using microsatellite markers[J]. Invest Ophthalmol Vis Sci, 2004, 45(12): 4433-4439. DOI: 10.1167/iovs.04-0544.
9. Hagstrom SA, Watson RF, Pauer GJ, et al. Tulp1 is involved in specific photoreceptor protein transport pathways[J]. Adv Exp Med Biol, 2012, 723: 783-789. DOI: 10.1007/978-1-4614-0631-0_100.
10. Grossman GH, Pauer GJ, Narendra U, et al. Early synaptic defects in tulp1^-/- mice[J]. Invest Ophthalmol Vis Sci, 2009, 50(7): 3074-3083. DOI: 10.1167/iovs.08-3190.
11. Hosch J, Lorenz B, Stieger K. RPGR: role in the photoreceptor cilium, human retinal disease, and gene therapy[J]. Ophthalmic Genet, 2011, 32(1): 1-11. DOI: 10.3109/13816810.2010.535889.
12. Khan AO, Abu-Safieh L, Eisenberger T, et al. The RPGRIP1-related retinal phenotype in children[J]. Br J Ophthalmol, 2013, 97(6): 760-764. DOI: 10.1136/bjophthalmol-2012-303050.
13. 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.
14. 王淑然. Leber先天性黑矇致病基因及相关临床表型研究进展[J]. 中华实验眼科杂志, 2013, 31(12): 1178-1182. DOI: 10.3760/cma.j.issn.2095-0160.2013.12.018.Wang SR. Current advance in genetics and clinical phenotype of Leber congenital amaurosis[J]. Chin J Exp Ophthalmol, 2013, 31(12): 1178-1182. DOI: 10.3760/cma.j.issn.2095-0160.2013.12.018.
15. Eisenberger T, Neuhaus C, Khan AO, et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies[J/OL]. PLoS One, 2013, 8(11): e78496[2013-11-12]. https://doi.org/10.1371/journal.pone.0078496. DOI: 10.1371/journal.pone.0078496.

Chinese Journal of Ocular Fundus Diseases

Clinical manifestations and genetic analysis of six different families of Leber's congenital amaurosis

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