Genotypes and phenotypes analysis of a novel complex heterozygous mutation of <i>CEP290</i> related isolated cone-rod dystrophy_Chinese Journal of Ocular Fundus Diseases

Authors：

Guo Qingge , Li Ya , You Ya , Liu Changgeng , Li Shuyin ,  Lei Bo

Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, China;

Corresponding author：

Lei Bo, Email: bolei99@126.com

Keywords：

Genes; Mutation; Cone-rod dystrophy; Clinical phenotype; CEP290 gene

DOI：

10.3760/cma.j.cn511434-20220706-00396

Video：

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Objective The clinical phenotypes and pathogenicity of isolated cone-rod dystrophy (CORD) caused by two novel complex heterozygous variants of the CEP290 gene were analyzed using high-resolution multi-mode imaging and gene detection techniques. Methods A retrospective study. Two patients and two family members from a CORD family who were diagnosed by genetic testing at Henan Provincial People's Hospital in December 2021 were included in the study. All subjects underwent best-corrected visual acuity (BCVA), color fundus photography, autofluorescence, swept-source optical coherence tomography (SS-OCT), adaptive optics fundus imaging, static threshold field, full field and multiple electroretinogram (ERG) examination, as well as other systemic examinations throughout the body. The peripheral venous blood of the subjects was collected, and the whole genome DNA was extracted. DNA sequencing was performed using the Inherited Retinal Disease Kit PS400, and Sanger verification and pedigree co-segregation analysis were performed on the suspected pathogenic mutation sites. Validation was performed by Sanger sequencing, pathogenicity analysis was performed in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. Conservation of variation among different species was analyzed by GERP++, Clustal Omega and Weblogo. Results Both patients were male, and their ages were 21 and 29 years old, respectively. The right eye and left eye about BCVAs were 0.7, 0.4 and 0.3, 0.4, respectively. The full field and multiple electroretinogram ERG showed a decreased function of cones and rods, especially cones. SS-OCT showed thinning of the outer nuclear layer of macular, and attenuation of ellipsoid zone reflectivity in B-scan. Adaptive optics fundus imaging examination showed that the arrangement of cone cells in the fovea of the fovea was disordered and the density decreased, and the retinal pigment epithelial cells were seen through the atrophy of cone cells in some areas at 10°visual angle. No obvious abnormality was found in other systemic examinations of the whole body. Genetic testing showed that 2 novel compound heterozygous variants c.950T >A (p.Leu317*) (M1) and c.4144_4149del (p.Tyr1382_Glu1383del) (M2) in CEP290 were found in two patients. The first variant was predicted to be harmful in MutationTaster and CADD. GERP++ showed highly conserved among different species. The pathogenicity of the variant was suspected to be likely pathogenic according to ACMG guidelines. The pathogenicity of the second variant was uncertain significance. The parents of the proband had no similar ocular abnormalities. Verified by Sanger sequencing, it was consistent with co-separation in the family. Conclusions Patients with pure CORD caused by CEP290 gene mutation still retain better vision when the cone structure is abnormal, the density is decreased, and the function of cone and rod cells is decreased. CEP290 M1 and M2 are newly discovered nonsense mutations and newly discovered deletion mutations, which expanded the causative gene spectrum of pure CORD.

Citation： Guo Qingge, Li Ya, You Ya, Liu Changgeng, Li Shuyin, Lei Bo. Genotypes and phenotypes analysis of a novel complex heterozygous mutation of CEP290 related isolated cone-rod dystrophy. Chinese Journal of Ocular Fundus Diseases, 2022, 38(8): 650-655. doi: 10.3760/cma.j.cn511434-20220706-00396 Copy

1.	Chen BB, Zhai Y, Huo YN, et al. A novel CEP290 disease-causing variant identified in a patient with leber congenital amaurosis using a medical diagnostic panel sequencing[J]. Ophthalmic Genet, 2022, 43(1): 97-103. DOI: 10.1080/13816810.2021.2004431.
2.	Testa F, Sodi A, Signorini S, et al. Spectrum of disease severity in nonsyndromic patients with mutations in the CEP290 gene: a multicentric longitudinal study[J]. Invest Ophthalmol Vis Sci, 2021, 62(9): 1. DOI: 10.1167/iovs.62.9.1.
3.	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.
4.	Yzer S, Hollander AI, Lopez I, et al. Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290[J]. Mol Vis, 2012, 18: 412-425.
5.	Littink KW, Pott JW, Collin RW, et al. A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype[J]. Invest Ophthalmol Vis Sci, 2010, 51(7): 3646-3652. DOI: 10.1167/iovs.09-5074.
6.	Vilaplana F, Ros A, Garcia B, et al. Clinical characteristics, imaging findings, and genetic results of a patient with CEP290-related cone-rod dystrophy[J]. Ophthalmic Genet, 2021, 42(4): 474-479. DOI: 10.1080/13816810.2021.1916827.
7.	Ge Z, Bowles K, Goetz K, et al. NGS-based molecular diagnosis of 105 eyeGENE(®) probands with retinitis pigmentosa[J/OL]. Sci Rep, 2015, 5: 18287[2015-12-15]. https://pubmed.ncbi.nlm.nih.gov/26667666/. DOI: 10.1038/srep18287.
8.	Vámos R, Külm M, Szabó V, et al. Leber congenital amaurosis: first genotyped Hungarian patients and report of 2 novel mutations in the CRB1 and CEP290 genes[J]. Eur J Ophthalmol, 2016, 26(1): 78-84. DOI: 10.5301/ejo.5000643.
9.	Roosing S, Cremers F, Riemslag F, et al. A rare form of retinal dystrophy caused by hypomorphic nonsense mutations in CEP290[J]. Genes (Basel), 2017, 8(8): 208. DOI: 10.3390/genes8080208.
10.	Coppieters F, Casteels I, Meire F, et al. Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes[J/OL]. Hum Mutat, 2010, 31(10): e1709-1766[2010-10-01]. https://pubmed.ncbi.nlm.nih.gov/20683928/. DOI: 10.1002/humu.21336.
11.	Perrault I, Delphin N, Hanein S, et al. Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype[J]. Hum Mutat, 2007, 28(4): 416. DOI: 10.1002/humu.9485.
12.	Guo Q, Li Y, Li J, et al. Phenotype heterogeneity and the association between visual acuity and outer retinal structure in a cohort of Chinese X-linked juvenile retinoschisis patients[J/OL]. Front Genet, 2022, 13: 832814[2022-05-04]. https://pubmed.ncbi.nlm.nih.gov/35309139/. DOI: 10.3389/fgene.2022.832814.
13.	Fu L, Li Y, Yao S, et al. Autosomal recessive rod-cone dystrophy associated with compound heterozygous variants in ARL3 gene[J/OL]. Front Cell Dev Biol, 2021, 9: 635424[2021-03-04]. https://pubmed.ncbi.nlm.nih.gov/33748123/. DOI: 10.3389/fcell.2021.635424.
14.	Zhang L, Li Y, Qin L, et al. Autosomal recessive retinitis pigmentosa associated with three novel REEP6 variants in Chinese population[J]. Genes (Basel), 2021, 12(4): 537. DOI: 10.3390/genes12040537.
15.	Zhu Q, Rui X, Li Y, et al. Identification of four novel variants and determination of genotype-phenotype correlations for ABCA4 variants associated with inherited retinal degenerations[J/OL]. Front Cell Dev Biol, 2021, 9: 634843[2021-03-01]. https://pubmed.ncbi.nlm.nih.gov/33732702/. DOI: 10.3389/fcell.2021.634843.
16.	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.
17.	Pasadhika S, Fishman GA, Stone EM, et al. Differential macular morphology in patients with RPE65-, CEP290-, GUCY2D-, and AIPL1-related Leber congenital amaurosis[J]. Invest Ophthalmol Vis Sci, 2010, 51(5): 2608-2614. DOI: 10.1167/iovs.09-3734.
18.	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.
19.	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.
20.	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.
21.	Sheck L, Davies W, Moradi P, et al. Leber congenital amaurosis associated with mutations in CEP290, clinical phenotype, and natural history in preparation for trials of novel therapies[J]. Ophthalmology, 2018, 125(6): 894-903. DOI: 10.1016/j.ophtha.2017.12.013.
22.	Jacobson SG, Cideciyan AV, Sumaroka A, et al. Outcome measures for clinical trials of Leber congenital amaurosis caused by the intronic mutation in the CEP290 gene[J]. Invest Ophthalmol Vis Sci, 2017, 58(5): 2609-2622. DOI: 10.1167/iovs.17-21560.
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.	Rafalska A, Tracewska AM, Turno-Krecicka A, et al. A mild phenotype caused by two novel compound heterozygous mutations in CEP290[J/OL]. Genes (Basel), 2020, 11(11): 1240[2020-10-22]. https://pubmed.ncbi.nlm.nih.gov/33105651/. DOI: 10.3390/genes11111240.
25.	Barny I, Perrault I, Rio M, et al. Description of two siblings with apparently severe CEP290 mutations and unusually mild retinal disease unrelated to basal exon skipping or nonsense-associated altered splicing[J]. Adv Exp Med Biol, 2019, 1185: 189-195. DOI: 10.1007/978-3-030-27378-1_31.
26.	Birtel J, Gliem M, Mangold E, et al. Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa[J/OL]. PLoS One, 2018, 13(12): e207958[2018-12-13]. https://pubmed.ncbi.nlm.nih.gov/30543658/. DOI: 10.1371/journal.pone.0207958.
27.	Preising MN, Schneider U, Friedburg C, et al. The phenotypic spectrum of ophthalmic changes in CEP290 mutations[J]. Klin Monbl Augenheilkd, 2019, 236(3): 244-252. DOI: 10.1055/a-0842-3250.
28.	Mcanany JJ, Genead MA, Walia S, et al. Visual acuity changes in patients with leber congenital amaurosis and mutations in CEP290[J]. JAMA Ophthalmol, 2013, 131(2): 178-182. DOI: 10.1001/2013.jamaophthalmol.354.
29.	Barny I, Perrault I, Michel C, et al. Basal exon skipping and nonsense-associated altered splicing allows bypassing complete CEP290 loss-of-function in individuals with unusually mild retinal disease[J]. Hum Mol Genet, 2018, 27(15): 2689-2702. DOI: 10.1093/hmg/ddy179.
30.	Williamson M, Traboulsi E, Debenedictis M. Investigation of CEP290 genotype-phenotype correlations in a patient with retinitis pigmentosa, infertility, end-stage renal disease, and a novel mutation[J]. Ophthalmic Genet, 2020, 41(2): 171-174. DOI: 10.1080/13816810.2020.1744017.
31.	Burnight ER, Wiley LA, Drack AV, et al. CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype[J]. Gene Ther, 2014, 21(7): 662-672. DOI: 10.1038/gt.2014.39.

1. Chen BB, Zhai Y, Huo YN, et al. A novel CEP290 disease-causing variant identified in a patient with leber congenital amaurosis using a medical diagnostic panel sequencing[J]. Ophthalmic Genet, 2022, 43(1): 97-103. DOI: 10.1080/13816810.2021.2004431.
2. Testa F, Sodi A, Signorini S, et al. Spectrum of disease severity in nonsyndromic patients with mutations in the CEP290 gene: a multicentric longitudinal study[J]. Invest Ophthalmol Vis Sci, 2021, 62(9): 1. DOI: 10.1167/iovs.62.9.1.
3. 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.
4. Yzer S, Hollander AI, Lopez I, et al. Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290[J]. Mol Vis, 2012, 18: 412-425.
5. Littink KW, Pott JW, Collin RW, et al. A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype[J]. Invest Ophthalmol Vis Sci, 2010, 51(7): 3646-3652. DOI: 10.1167/iovs.09-5074.
6. Vilaplana F, Ros A, Garcia B, et al. Clinical characteristics, imaging findings, and genetic results of a patient with CEP290-related cone-rod dystrophy[J]. Ophthalmic Genet, 2021, 42(4): 474-479. DOI: 10.1080/13816810.2021.1916827.
7. Ge Z, Bowles K, Goetz K, et al. NGS-based molecular diagnosis of 105 eyeGENE(®) probands with retinitis pigmentosa[J/OL]. Sci Rep, 2015, 5: 18287[2015-12-15]. https://pubmed.ncbi.nlm.nih.gov/26667666/. DOI: 10.1038/srep18287.
8. Vámos R, Külm M, Szabó V, et al. Leber congenital amaurosis: first genotyped Hungarian patients and report of 2 novel mutations in the CRB1 and CEP290 genes[J]. Eur J Ophthalmol, 2016, 26(1): 78-84. DOI: 10.5301/ejo.5000643.
9. Roosing S, Cremers F, Riemslag F, et al. A rare form of retinal dystrophy caused by hypomorphic nonsense mutations in CEP290[J]. Genes (Basel), 2017, 8(8): 208. DOI: 10.3390/genes8080208.
10. Coppieters F, Casteels I, Meire F, et al. Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes[J/OL]. Hum Mutat, 2010, 31(10): e1709-1766[2010-10-01]. https://pubmed.ncbi.nlm.nih.gov/20683928/. DOI: 10.1002/humu.21336.
11. Perrault I, Delphin N, Hanein S, et al. Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype[J]. Hum Mutat, 2007, 28(4): 416. DOI: 10.1002/humu.9485.
12. Guo Q, Li Y, Li J, et al. Phenotype heterogeneity and the association between visual acuity and outer retinal structure in a cohort of Chinese X-linked juvenile retinoschisis patients[J/OL]. Front Genet, 2022, 13: 832814[2022-05-04]. https://pubmed.ncbi.nlm.nih.gov/35309139/. DOI: 10.3389/fgene.2022.832814.
13. Fu L, Li Y, Yao S, et al. Autosomal recessive rod-cone dystrophy associated with compound heterozygous variants in ARL3 gene[J/OL]. Front Cell Dev Biol, 2021, 9: 635424[2021-03-04]. https://pubmed.ncbi.nlm.nih.gov/33748123/. DOI: 10.3389/fcell.2021.635424.
14. Zhang L, Li Y, Qin L, et al. Autosomal recessive retinitis pigmentosa associated with three novel REEP6 variants in Chinese population[J]. Genes (Basel), 2021, 12(4): 537. DOI: 10.3390/genes12040537.
15. Zhu Q, Rui X, Li Y, et al. Identification of four novel variants and determination of genotype-phenotype correlations for ABCA4 variants associated with inherited retinal degenerations[J/OL]. Front Cell Dev Biol, 2021, 9: 634843[2021-03-01]. https://pubmed.ncbi.nlm.nih.gov/33732702/. DOI: 10.3389/fcell.2021.634843.
16. 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.
17. Pasadhika S, Fishman GA, Stone EM, et al. Differential macular morphology in patients with RPE65-, CEP290-, GUCY2D-, and AIPL1-related Leber congenital amaurosis[J]. Invest Ophthalmol Vis Sci, 2010, 51(5): 2608-2614. DOI: 10.1167/iovs.09-3734.
18. 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.
19. 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.
20. 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.
21. Sheck L, Davies W, Moradi P, et al. Leber congenital amaurosis associated with mutations in CEP290, clinical phenotype, and natural history in preparation for trials of novel therapies[J]. Ophthalmology, 2018, 125(6): 894-903. DOI: 10.1016/j.ophtha.2017.12.013.
22. Jacobson SG, Cideciyan AV, Sumaroka A, et al. Outcome measures for clinical trials of Leber congenital amaurosis caused by the intronic mutation in the CEP290 gene[J]. Invest Ophthalmol Vis Sci, 2017, 58(5): 2609-2622. DOI: 10.1167/iovs.17-21560.
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. Rafalska A, Tracewska AM, Turno-Krecicka A, et al. A mild phenotype caused by two novel compound heterozygous mutations in CEP290[J/OL]. Genes (Basel), 2020, 11(11): 1240[2020-10-22]. https://pubmed.ncbi.nlm.nih.gov/33105651/. DOI: 10.3390/genes11111240.
25. Barny I, Perrault I, Rio M, et al. Description of two siblings with apparently severe CEP290 mutations and unusually mild retinal disease unrelated to basal exon skipping or nonsense-associated altered splicing[J]. Adv Exp Med Biol, 2019, 1185: 189-195. DOI: 10.1007/978-3-030-27378-1_31.
26. Birtel J, Gliem M, Mangold E, et al. Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa[J/OL]. PLoS One, 2018, 13(12): e207958[2018-12-13]. https://pubmed.ncbi.nlm.nih.gov/30543658/. DOI: 10.1371/journal.pone.0207958.
27. Preising MN, Schneider U, Friedburg C, et al. The phenotypic spectrum of ophthalmic changes in CEP290 mutations[J]. Klin Monbl Augenheilkd, 2019, 236(3): 244-252. DOI: 10.1055/a-0842-3250.
28. Mcanany JJ, Genead MA, Walia S, et al. Visual acuity changes in patients with leber congenital amaurosis and mutations in CEP290[J]. JAMA Ophthalmol, 2013, 131(2): 178-182. DOI: 10.1001/2013.jamaophthalmol.354.
29. Barny I, Perrault I, Michel C, et al. Basal exon skipping and nonsense-associated altered splicing allows bypassing complete CEP290 loss-of-function in individuals with unusually mild retinal disease[J]. Hum Mol Genet, 2018, 27(15): 2689-2702. DOI: 10.1093/hmg/ddy179.
30. Williamson M, Traboulsi E, Debenedictis M. Investigation of CEP290 genotype-phenotype correlations in a patient with retinitis pigmentosa, infertility, end-stage renal disease, and a novel mutation[J]. Ophthalmic Genet, 2020, 41(2): 171-174. DOI: 10.1080/13816810.2020.1744017.
31. Burnight ER, Wiley LA, Drack AV, et al. CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype[J]. Gene Ther, 2014, 21(7): 662-672. DOI: 10.1038/gt.2014.39.

Chinese Journal of Ocular Fundus Diseases

Genotypes and phenotypes analysis of a novel complex heterozygous mutation of CEP290 related isolated cone-rod dystrophy

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