Phenotypic analysis of patients with Leber congenital amaurosis caused by new gene mutations_Chinese Journal of Ocular Fundus Diseases

Authors：

Fang Xinhe ¹ , Zhu Yan ¹ , Yuan Shiqin ¹ , Rong Weining ¹ , Wang Xiaoguang ¹ , Rui Xue ² , Ma Meijiao ² ,  Sheng Xunlun ^1,2

1. Ning Xia Eye Hospital of People's Hospital of Ningxia Hui Autonomous Region, First Affiliated Hospital of Northwest University for Nationalities, Yinchun 750001, China;
2. Gansu Aier Optometry Hospital, Lanzhou 730050, China;

Corresponding author：

Sheng Xunlun, Email: shengxunlun@163.com

Keywords：

Leber congenital amaurosis; Genes; Mutation; Clinical phenotype; PRPH2 gene; TULP1 gene; GUCY2D gene

DOI：

10.3760/cma.j.cn511434-20220406-00192

Video：

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Objective To identify 3 the disease-causing genes and mutations of Leber congenital amaurosis (LCA), and to study the correlation of phenotype and genotype. Methods A retrospective study. Four LCA patients and seven family members who were diagnosed by eye examination in Ning Xia Eye Hospital of People's Hospital of Ningxia Hui Autonomous Region from January to December 2021 were included in the study. Four patients were from 3 unrelated families. Detailed collection of medical history and family history were received. Related ophthalmologic examination were collected and genomic DNA was extracted from peripheral blood. Whole-exome sequencing method was used for genetic diagnosis. The identified variant was confirmed with Sanger sequencing. Potential pathogenic mutation was analyzed using software and conserved domain analysis and performed co-separated analysis between the family member and the proband. Results Of the 4 patients, 1 patient was males and 3 patients were females; the age was from 4 to 18 years. Nystagmus were seen in 3 cases, finger pressing eyes and night blindness was seen in 1 cases; electroretinogram showed 4 cases of extinction or near extinction. The foveal reflection was visible in all eyes, and there was no obvious abnormality in the peripheral retina. One eye had strong reflection signal with raised ellipsoid in macular area; two eyes had weak reflection signal faintly visible between retinal layers; 1 eye had increased blood vessel branches, peripheral retinal non-perfusion area with capillary leakage; annular strong autofluorescence in macular area 4 eyes. No obvious abnormality was found in the phenotypes of family members. Genetic testing showed that the proband of pedigree 1 (Ⅱ-1) was found a homozygous missense mutation in c.640A>T (p.C214S) (M1) of PRPH2 gene. The proband of pedigree 2 (Ⅱ-2) was found compound heterozygous mutation in c.1256G>A(p.R419Q) (M2) and c.1A>C (p.M1L) (M3) of TULP1 gene. The proband 3 (Ⅱ-1) and her sister (Ⅱ-2) were both found compound heterozygous mutation in c.1943T>C (p.L648P) (M4) and c.380C>T (p.P127L) (M5) of GUCY2D gene. The parents and sister (Ⅱ-1) of the proband in family 2 and the parents of the proband in family 3 were all carriers of the corresponding heterozygous variant. M1, M3, M4, M5 were novel mutations and unreported. The genotype and disease phenotype were co-segregated within the family. According to the analysis of pedigree and genetic testing results, all 3 families were autosomal recessive inheritance. The amino acid conservation analysis found that M1, M2, M3, M4, and M5 were highly conserved among species. The results of bioinformatics analysis were all pathogenic variants. Conclusions PRPH2 gene M1, TULP1 gene M3, and GUCY2D gene M4, M5 were novel mutations and not been reported in the literature and database. This research expanded the gene mutation spectrum of LCA. The patients with LCA have available characterristics, including onset age, varying ocular fundus and severe visual impairment.

Citation： Fang Xinhe, Zhu Yan, Yuan Shiqin, Rong Weining, Wang Xiaoguang, Rui Xue, Ma Meijiao, Sheng Xunlun. Phenotypic analysis of patients with Leber congenital amaurosis caused by new gene mutations. Chinese Journal of Ocular Fundus Diseases, 2022, 38(8): 668-674. doi: 10.3760/cma.j.cn511434-20220406-00192 Copy

1.	Tan MH, Mackay DS, Cowing J, et al. Leber congenital amaurosis associated with AIPL1: challenges in ascribing disease causation, clinical findings, and implications for gene therapy[J/OL]. PLoS One, 2012, 7(3): e32330[2012-03-06]. https://pubmed.ncbi.nlm.nih.gov/22412862/. DOI: 10.1371/journal.pone.0032330.
2.	睢瑞芳, 赵潺, 姜茹欣, 等. Leber先天黑矇的临床研究[J]. 中华眼底病杂志, 2009, 25(6): 443-446. DOI: 10.3760/cma.j.issn.1015-1005.2009.06.10.Sui RF, Zhao C, Jing RX, et al. Clinical study on Leber congenital amaurosis[J]. Chin J Ocul Fundus Dis, 2009, 25(6): 443-446. DOI: 10.3760/cma.j.issn.1015-1005.2009.06.10.
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4.	Wang X, Yu C, Tzekov RT, et al. The effect of human gene therapy for RPE65-associated Leber's congenital amaurosis on visual function: a systematic review and metaanalysis[J]. Orphanet J Rare Dis, 2020, 15(1): 49. DOI: 10.1186/s13023-020-1304-1.
5.	Austin CP, Cutillo CM, Lau LP, et al. Future of rare diseases research 2017-2027: an IRDiRC perspective[J]. Clin Transl Sci, 2018, 11(1): 21-27. DOI: 10.1111/cts.12500.
6.	邹绚, 睢瑞芳. Leber先天黑矇基因型与临床表型的相关性研究[D]. 北京: 北京协和医院, 2012.Zou X, Sui RF. Correlation between Leber congenital amaurosis genotype and clinical phenotype[D]. Beijing: Peking Union Medical College Hospital, 2012.
7.	房心荷, 张芳霞, 朱艳, 等. 应用目标基因捕获结合二代测序技术检测无遗传性眼病家族史的遗传性视网膜疾病患者的致病基因[J]. 中华实验眼科杂志, 2017, 12(35): 1097-1103. DOI: 10.3760/cma.j.issn.2095-0160.2017.12.009.Fang XH, Zhang FX, Zhu Y, et al. Rapid identification of pathogenic mutations in sporadic hereditary retinal dystrophies using targeted nextgeneration sequencing[J]. Chin J Exp Ophthalmol, 2017, 12(35): 1097-1103. DOI: 10.3760/cma.j.issn.2095-0160.2017.12.009.
8.	王秋菊, 沈亦平, 邬玲仟, 等. 遗传变异分类标准与指南[J]. 中国科学 (生命科学), 2017, 47(6): 668-688. DOI: 10.1360/N052017-00099.Wang QJ, Shen YP, Wu LQ, et al. Standards and guidelines for the interpretation of sequence variants[J]. Science in China (Series C), 2017, 47(6): 668-688. DOI: 10.1360/N052017-00099.
9.	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.
10.	Xu K, Xie Y, Sun T, et al. Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy[J]. Br J Ophthalmol, 2020, 104(7): 932-937. DOI: 10.1136/bjophthalmol-2019-314281.
11.	Minegishi Y, Sheng X, Yoshitake K, et al. CCT2 mutations evoke Leber congenital amaurosis due to chaperone complex instability[J/OL]. Sci Rep, 2016, 6: 33742[2016-09-20]. https://pubmed.ncbi.nlm.nih.gov/27645772/. DOI: 10.1038/srep33742.
12.	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.
13.	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.
14.	Wang X, Wang H, Sun V, et al. Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing[J]. J Med Genet, 2013, 50(10): 674-688. DOI: 10.1136/jmedgenet-2013-101558.
15.	Cideciyan AV, Jacobson SG. Leber congenital amaurosis (LCA): potential for improvement of vision[J]. Invest Ophthalmol Vis Sci, 2019, 60(5): 1680-1695. DOI: 10.1167/iovs.19-26672.
16.	Becirovic E, Böhm S, Nguyen ON, et al. In vivo analysis of disease-associated point mutations unveils profound differences in mRNA splicing of peripherin-2 in rod and cone photoreceptors[J/OL]. PLoS Genet, 2016, 12(1): e1005811[2016-01-21]. https://pubmed.ncbi.nlm.nih.gov/26796962/. DOI: 10.1371/journal.pgen.1005811.
17.	Patel N, Aldahmesh MA, Alkuraya H, et al. Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies[J]. Genet Med, 2016, 18(6): 554-562. DOI: 10.1038/gim.2015.127.
18.	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.

1. Tan MH, Mackay DS, Cowing J, et al. Leber congenital amaurosis associated with AIPL1: challenges in ascribing disease causation, clinical findings, and implications for gene therapy[J/OL]. PLoS One, 2012, 7(3): e32330[2012-03-06]. https://pubmed.ncbi.nlm.nih.gov/22412862/. DOI: 10.1371/journal.pone.0032330.
2. 睢瑞芳, 赵潺, 姜茹欣, 等. Leber先天黑矇的临床研究[J]. 中华眼底病杂志, 2009, 25(6): 443-446. DOI: 10.3760/cma.j.issn.1015-1005.2009.06.10.Sui RF, Zhao C, Jing RX, et al. Clinical study on Leber congenital amaurosis[J]. Chin J Ocul Fundus Dis, 2009, 25(6): 443-446. DOI: 10.3760/cma.j.issn.1015-1005.2009.06.10.
3. Wang SY, Zhang Q, Zhang X, et al. Comprehensive analysis of genetic variations in strictly-defined Leber congenital amaurosis with whole-exome sequencing in Chinese[J]. Int J Ophthalmol, 2016, 9(9): 1260-1264. DOI: 10.18240/ijo.2016.09.04.
4. Wang X, Yu C, Tzekov RT, et al. The effect of human gene therapy for RPE65-associated Leber's congenital amaurosis on visual function: a systematic review and metaanalysis[J]. Orphanet J Rare Dis, 2020, 15(1): 49. DOI: 10.1186/s13023-020-1304-1.
5. Austin CP, Cutillo CM, Lau LP, et al. Future of rare diseases research 2017-2027: an IRDiRC perspective[J]. Clin Transl Sci, 2018, 11(1): 21-27. DOI: 10.1111/cts.12500.
6. 邹绚, 睢瑞芳. Leber先天黑矇基因型与临床表型的相关性研究[D]. 北京: 北京协和医院, 2012.Zou X, Sui RF. Correlation between Leber congenital amaurosis genotype and clinical phenotype[D]. Beijing: Peking Union Medical College Hospital, 2012.
7. 房心荷, 张芳霞, 朱艳, 等. 应用目标基因捕获结合二代测序技术检测无遗传性眼病家族史的遗传性视网膜疾病患者的致病基因[J]. 中华实验眼科杂志, 2017, 12(35): 1097-1103. DOI: 10.3760/cma.j.issn.2095-0160.2017.12.009.Fang XH, Zhang FX, Zhu Y, et al. Rapid identification of pathogenic mutations in sporadic hereditary retinal dystrophies using targeted nextgeneration sequencing[J]. Chin J Exp Ophthalmol, 2017, 12(35): 1097-1103. DOI: 10.3760/cma.j.issn.2095-0160.2017.12.009.
8. 王秋菊, 沈亦平, 邬玲仟, 等. 遗传变异分类标准与指南[J]. 中国科学 (生命科学), 2017, 47(6): 668-688. DOI: 10.1360/N052017-00099.Wang QJ, Shen YP, Wu LQ, et al. Standards and guidelines for the interpretation of sequence variants[J]. Science in China (Series C), 2017, 47(6): 668-688. DOI: 10.1360/N052017-00099.
9. 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.
10. Xu K, Xie Y, Sun T, et al. Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy[J]. Br J Ophthalmol, 2020, 104(7): 932-937. DOI: 10.1136/bjophthalmol-2019-314281.
11. Minegishi Y, Sheng X, Yoshitake K, et al. CCT2 mutations evoke Leber congenital amaurosis due to chaperone complex instability[J/OL]. Sci Rep, 2016, 6: 33742[2016-09-20]. https://pubmed.ncbi.nlm.nih.gov/27645772/. DOI: 10.1038/srep33742.
12. 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.
13. 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.
14. Wang X, Wang H, Sun V, et al. Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing[J]. J Med Genet, 2013, 50(10): 674-688. DOI: 10.1136/jmedgenet-2013-101558.
15. Cideciyan AV, Jacobson SG. Leber congenital amaurosis (LCA): potential for improvement of vision[J]. Invest Ophthalmol Vis Sci, 2019, 60(5): 1680-1695. DOI: 10.1167/iovs.19-26672.
16. Becirovic E, Böhm S, Nguyen ON, et al. In vivo analysis of disease-associated point mutations unveils profound differences in mRNA splicing of peripherin-2 in rod and cone photoreceptors[J/OL]. PLoS Genet, 2016, 12(1): e1005811[2016-01-21]. https://pubmed.ncbi.nlm.nih.gov/26796962/. DOI: 10.1371/journal.pgen.1005811.
17. Patel N, Aldahmesh MA, Alkuraya H, et al. Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies[J]. Genet Med, 2016, 18(6): 554-562. DOI: 10.1038/gim.2015.127.
18. 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.

Chinese Journal of Ocular Fundus Diseases

Phenotypic analysis of patients with Leber congenital amaurosis caused by new gene mutations

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