Analysis of <i>CEP290</i> gene variants and clinical phenotypes in a family with Leber congenital amaurosis type 10_Chinese Journal of Ocular Fundus Diseases

Authors：

 Zhang Haitao ¹ , Zhu Ziqian ¹ , Dan Handong ¹ , Xu Yingying ¹ , Guo Hanchao ² , Shi Lu ^3,4 , Mao Liangwei ³

1. Department of Ophthalmology, Henan Provincial People's Hospital, Henan Eye Hospital, Henan Eye Institute, People's Hospital of Zhengzhou University, Zhengzhou 450003, China;
2. Department of Ophthalmology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;
3. Department of Medicine, Wuhan Primbio Medical Laboratory, Wuhan 430075, China;
4. Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China;

Corresponding author：

Zhang Haitao, Email: zhanght525@163.com

Keywords：

Leber congenital amaurosis type 10; CEP290 gene; Whole exome sequencing; Minigene splicing assay

DOI：

10.3760/cma.j.cn511434-20231012-00415

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Objective To identify and observe disease-causing gene variants and clinical phenotypes in a Han Chinese family with Leber congenital amaurosis (LCA). Methods A retrospective study. A patient with LCA10 and his parents who had presented at Department of Ophthalmology of Henan Provincial People's Hospital on May 2022 were selected as the study subject. Detailed medical and family histories were recorded, fundus photography and flash electroretinogram (F-ERG) were performed. Peripheral venous blood samples (3 ml) of the proband and his parents were collected to extract whole genomic DNA, then whole exome sequencing (WES) and mitochondrial DNA (mtDNA) sequencing were carried out for the proband to determine the disease-causing gene and variants. All variants were annotated by bioinformatics analysis. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the pathogenicity of all detected variants were evaluated. Candidate variants were verified by Sanger sequencing, and in vitro minigene assay were performed to evaluate the impact of the missense variant with insufficient evidence on mRNA splicing. Results The proband, male, 7-month-old, presented with an inability to follow light or objects, eye poking, photophobia, nystagmus, partial loss of retinal pigment epithelium around the fovea of the macula. At the age of 2 years old, F-ERG revealed severe reduction, elongation, or even no waveform of a-wave and b-wave in both eyes. No obvious abnormality was found in the clinical phenotype of his parents. The result of WES revealed that the proband carried two variants in exon 40 and exon 2 of CEP290, a frameshift variant c.5515_5518del (p.Glu1839Lysfs*11) (V1) and a novel missense variant c.74C>T (p.Ala25Val) (V2), respectively. The result of mitochondrial DNA sequencing was negative. Sanger sequencing confirmed that the heterozygous frameshift variant was inherited from his father and the heterozygous novel missense variant was inherited from his mother, which constituted compound heterozygous variants. In vitro minigene splicing assay confirmed that V2 created a new splicing donor at exon 2, leading to the in-frame deletion of 30bp fragment during transcription and loss of 10 amino acid residues in the protein. The two variants were pathogenic (V1) and likely pathogenic (V2) based on ACMG guidelines, respectively. Conclusions The c.5515_5518del and novel c.74C>T compound heterozygous variants of the CEP290 gene probably are the cause of LCA10 in this family, which lead to the production of a truncated protein and aberrant splicing of pre-mRNA, respectively. LCA is characterized by early onset, severe impairment of visual function, and a wide range of disease-causing variations.

Citation： Zhang Haitao, Zhu Ziqian, Dan Handong, Xu Yingying, Guo Hanchao, Shi Lu, Mao Liangwei. Analysis of CEP290 gene variants and clinical phenotypes in a family with Leber congenital amaurosis type 10. Chinese Journal of Ocular Fundus Diseases, 2024, 40(4): 273-280. doi: 10.3760/cma.j.cn511434-20231012-00415 Copy

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2.	Stone EM. Leber congenital amaurosis-a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture[J]. Am J Ophthalmol, 2007, 144(6): 791-811. DOI: 10.1016/j.ajo.2007.08.022.
3.	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.
4.	Den Hollander AI, Koenekoop RK, Yzer S, et al. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis[J]. Am J Hum Genet, 2006, 79(3): 556-561. DOI: 10.1086/507318.
5.	Mcewen DP, Koenekoop RK, Khanna H, et al. Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons[J]. Proc Natl Acad Sci USA, 2007, 104(40): 15917-15922. DOI: 10.1073/pnas.0704140104.
6.	Coppieters F, Lefever S, Leroy BP, et al. CEP290, a gene with many faces: mutation overview and presentation of CEP290base[J]. Hum Mutat, 2010, 31(10): 1097-1108. DOI: 10.1002/humu.21337.
7.	Sayer JA, Otto EA, O'toole JF, et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4[J]. Nat Genet, 2006, 38(6): 674-681. DOI: 10.1038/ng1786.
8.	Badano JL, Mitsuma N, Beales PL, et al. The ciliopathies: an emerging class of human genetic disorders[J]. Annu Rev Genomics Hum Genet, 2006, 7: 125-148. DOI: 10.1146/annurev.genom.7.080505.115610.
9.	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.
10.	Skorczyk-Werner A, Niedziela Z, Stopa M, et al. Novel gene variants in polish patients with Leber congenital amaurosis (LCA)[J]. Orphanet J Rare Dis, 2020, 15(1): 345. DOI: 10.1186/s13023-020-01634-y.
11.	中国眼遗传病诊疗小组, 中国眼科遗传联盟. Leber先天黑矇诊疗的中国专家共识(2023)[J]. 中国实验眼科杂志, 2023, 41(9): 833-842. DOI: 10.3760/cma.j.cn115989-20230523-00188.Chinese Hereditary Ocular Disease Diagnosis and Treatment Group, Chinese Hereditary Ocular Disease Alliance. Chinese expert consensus on diagnosis and treatment of Leber congenital amaurosis (2023)[J]. Chin J Exp Ophthalmol, 2023, 41(9): 833-842. DOI: 10.3760/cma.j.cn115989-20230523-00188.
12.	Huang CH, Yang CM, Yang CH, et al. Leber's congenital amaurosis: current concepts of genotype-phenotype correlations[J]. Genes (Basel), 2021, 12(8): 1261. DOI: 10.3390/genes12081261.
13.	Papon JF, Perrault I, Coste A, et al. Abnormal respiratory cilia in non-syndromic Leber congenital amaurosis with CEP290 mutations[J]. J Med Genet, 2010, 47(12): 829-834. DOI: 10.1136/jmg.2010.077883.
14.	Kobayashi T, Kim S, Lin YC, et al. The CP110-interacting proteins Talpid3 and CEP290 play overlapping and distinct roles in cilia assembly[J]. J Cell Biol, 2014, 204(2): 215-229. DOI: 10.1083/jcb.201304153.
15.	Frank V, Den Hollander AI, Bruchle NO, et al. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome[J]. Hum Mutat, 2008, 29(1): 45-52. DOI: 10.1002/humu.20614.
16.	Wu Z, Pang N, Zhang Y, et al. CEP290 is essential for the initiation of ciliary transition zone assembly[J/OL]. PLoS Biol, 2020, 18(12): e3001034[2020-12-28]. https://pubmed.ncbi.nlm.nih.gov/33370260/. DOI: 10.1371/journal.pbio.3001034.
17.	Leroy BP, Birch DG, Duncan JL, et al. Leber congenital amaurosis due to cep290 mutations-severe vision impairment with a high unmet medical need: a review[J]. Retina, 2021, 41(5): 898-907. DOI: 10.1097/IAE.0000000000003133.
18.	Wang J, Li S, Jiang Y, et al. Pathogenic variants in CEP290 or IQCB1 cause earlier-onset retinopathy in senior-loken syndrome compared to those in INVS, NPHP3, or NPHP4[J]. Am J Ophthalmol, 2023, 252: 188-204. DOI: 10.1016/j.ajo.2023.03.025.
19.	Doherty D. Joubert syndrome: insights into brain development, cilium biology, and complex disease[J]. Semin Pediatr Neurol, 2009, 16(3): 143-154. DOI: 10.1016/j.spen.2009.06.002.
20.	Baala L, Audollent S, Martinovic J, et al. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome[J]. Am J Hum Genet, 2007, 81(1): 170-179. DOI: 10.1086/519494.
21.	Vallespin E, Lopez-Martinez MA, Cantalapiedra D, et al. Frequency of CEP290 c. 2991_1655A>G mutation in 175 Spanish families affected with Leber congenital amaurosis and early-onset retinitis pigmentosa[J]. Mol Vis, 2007, 13: 2160-2162.
22.	Valkenburg D, Van Cauwenbergh C, Lorenz B, et al. Clinical characterization of 66 patients with congenital retinal disease due to the deep-intronic c. 2991+1655A>G mutation in CEP290[J]. Invest Ophthalmol Vis Sci, 2018, 59(11): 4384-4391. DOI: 10.1167/iovs.18-24817.
23.	Feldhaus B, Weisschuh N, Nasser F, et al. CEP290 mutation spectrum and delineation of the associated phenotype in a large German cohort: a monocentric study[J]. Am J Ophthalmol, 2020, 211: 142-150. DOI: 10.1016/j.ajo.2019.11.012.
24.	Sallum JMF, Motta FL, Arno G, et al. Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients[J]. Am J Med Genet C Semin Med Genet, 2020, 184(3): 728-752. DOI: 10.1002/ajmg.c.31828.
25.	Turkyilmaz A, Geckinli BB, Alavanda C, et al. Meckel-Gruber syndrome: clinical and molecular genetic profiles in two fetuses and review of the current literature[J]. Genet Test Mol Biomarkers, 2021, 25(6): 445-451. DOI: 10.1089/gtmb.2020.0311.

1. Koenekoop RK. An overview of Leber congenital amaurosis: a model to understand human retinal development[J]. Surv Ophthalmol, 2004, 49(4): 379-398. DOI: 10.1016/j.survophthal.2004.04.003.
2. Stone EM. Leber congenital amaurosis-a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture[J]. Am J Ophthalmol, 2007, 144(6): 791-811. DOI: 10.1016/j.ajo.2007.08.022.
3. 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.
4. Den Hollander AI, Koenekoop RK, Yzer S, et al. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis[J]. Am J Hum Genet, 2006, 79(3): 556-561. DOI: 10.1086/507318.
5. Mcewen DP, Koenekoop RK, Khanna H, et al. Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons[J]. Proc Natl Acad Sci USA, 2007, 104(40): 15917-15922. DOI: 10.1073/pnas.0704140104.
6. Coppieters F, Lefever S, Leroy BP, et al. CEP290, a gene with many faces: mutation overview and presentation of CEP290base[J]. Hum Mutat, 2010, 31(10): 1097-1108. DOI: 10.1002/humu.21337.
7. Sayer JA, Otto EA, O'toole JF, et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4[J]. Nat Genet, 2006, 38(6): 674-681. DOI: 10.1038/ng1786.
8. Badano JL, Mitsuma N, Beales PL, et al. The ciliopathies: an emerging class of human genetic disorders[J]. Annu Rev Genomics Hum Genet, 2006, 7: 125-148. DOI: 10.1146/annurev.genom.7.080505.115610.
9. 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.
10. Skorczyk-Werner A, Niedziela Z, Stopa M, et al. Novel gene variants in polish patients with Leber congenital amaurosis (LCA)[J]. Orphanet J Rare Dis, 2020, 15(1): 345. DOI: 10.1186/s13023-020-01634-y.
11. 中国眼遗传病诊疗小组, 中国眼科遗传联盟. Leber先天黑矇诊疗的中国专家共识(2023)[J]. 中国实验眼科杂志, 2023, 41(9): 833-842. DOI: 10.3760/cma.j.cn115989-20230523-00188.Chinese Hereditary Ocular Disease Diagnosis and Treatment Group, Chinese Hereditary Ocular Disease Alliance. Chinese expert consensus on diagnosis and treatment of Leber congenital amaurosis (2023)[J]. Chin J Exp Ophthalmol, 2023, 41(9): 833-842. DOI: 10.3760/cma.j.cn115989-20230523-00188.
12. Huang CH, Yang CM, Yang CH, et al. Leber's congenital amaurosis: current concepts of genotype-phenotype correlations[J]. Genes (Basel), 2021, 12(8): 1261. DOI: 10.3390/genes12081261.
13. Papon JF, Perrault I, Coste A, et al. Abnormal respiratory cilia in non-syndromic Leber congenital amaurosis with CEP290 mutations[J]. J Med Genet, 2010, 47(12): 829-834. DOI: 10.1136/jmg.2010.077883.
14. Kobayashi T, Kim S, Lin YC, et al. The CP110-interacting proteins Talpid3 and CEP290 play overlapping and distinct roles in cilia assembly[J]. J Cell Biol, 2014, 204(2): 215-229. DOI: 10.1083/jcb.201304153.
15. Frank V, Den Hollander AI, Bruchle NO, et al. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome[J]. Hum Mutat, 2008, 29(1): 45-52. DOI: 10.1002/humu.20614.
16. Wu Z, Pang N, Zhang Y, et al. CEP290 is essential for the initiation of ciliary transition zone assembly[J/OL]. PLoS Biol, 2020, 18(12): e3001034[2020-12-28]. https://pubmed.ncbi.nlm.nih.gov/33370260/. DOI: 10.1371/journal.pbio.3001034.
17. Leroy BP, Birch DG, Duncan JL, et al. Leber congenital amaurosis due to cep290 mutations-severe vision impairment with a high unmet medical need: a review[J]. Retina, 2021, 41(5): 898-907. DOI: 10.1097/IAE.0000000000003133.
18. Wang J, Li S, Jiang Y, et al. Pathogenic variants in CEP290 or IQCB1 cause earlier-onset retinopathy in senior-loken syndrome compared to those in INVS, NPHP3, or NPHP4[J]. Am J Ophthalmol, 2023, 252: 188-204. DOI: 10.1016/j.ajo.2023.03.025.
19. Doherty D. Joubert syndrome: insights into brain development, cilium biology, and complex disease[J]. Semin Pediatr Neurol, 2009, 16(3): 143-154. DOI: 10.1016/j.spen.2009.06.002.
20. Baala L, Audollent S, Martinovic J, et al. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome[J]. Am J Hum Genet, 2007, 81(1): 170-179. DOI: 10.1086/519494.
21. Vallespin E, Lopez-Martinez MA, Cantalapiedra D, et al. Frequency of CEP290 c. 2991_1655A>G mutation in 175 Spanish families affected with Leber congenital amaurosis and early-onset retinitis pigmentosa[J]. Mol Vis, 2007, 13: 2160-2162.
22. Valkenburg D, Van Cauwenbergh C, Lorenz B, et al. Clinical characterization of 66 patients with congenital retinal disease due to the deep-intronic c. 2991+1655A>G mutation in CEP290[J]. Invest Ophthalmol Vis Sci, 2018, 59(11): 4384-4391. DOI: 10.1167/iovs.18-24817.
23. Feldhaus B, Weisschuh N, Nasser F, et al. CEP290 mutation spectrum and delineation of the associated phenotype in a large German cohort: a monocentric study[J]. Am J Ophthalmol, 2020, 211: 142-150. DOI: 10.1016/j.ajo.2019.11.012.
24. Sallum JMF, Motta FL, Arno G, et al. Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients[J]. Am J Med Genet C Semin Med Genet, 2020, 184(3): 728-752. DOI: 10.1002/ajmg.c.31828.
25. Turkyilmaz A, Geckinli BB, Alavanda C, et al. Meckel-Gruber syndrome: clinical and molecular genetic profiles in two fetuses and review of the current literature[J]. Genet Test Mol Biomarkers, 2021, 25(6): 445-451. DOI: 10.1089/gtmb.2020.0311.

Chinese Journal of Ocular Fundus Diseases

Analysis of CEP290 gene variants and clinical phenotypes in a family with Leber congenital amaurosis type 10

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