Clinical features and genetic study of three patients with leber congenital amaurosis_West China Medical Journal

Authors：

ZHOU Qi ^1,2 , LI Ziyuan ^1,3 ,  LU Fang ¹

1. Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Ophthalmology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;
3. Department of Ophthalmology, Sichuan Provincial Hospital for Women and Children, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LU Fang, Email: 2391017644@qq.com

Keywords：

Leber congenital amaurosis; Phenotype; Genotype; Whole-exome sequencing; Genetic heterogeneity

DOI：

10.7507/1002-0179.201809128

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the genotype and phenotype in patients with leber congenital amaurosis (LCA), and offer accurate genetic counseling and prenatal diagnosis for those families. Methods Three LCA patients and their parents were recruited for this study and received detailed collection of medical history and family history from March to August 2016. The three patients received fundus fluorescein angiography examination and their parents received slit-lamp microscope and indirect ophthalmoscopy examinations. DNA was extracted from the patients and their family members. Whole-exome sequencing method was used for genetic diagnosis and typing of the three LCA patients and their parents. Results The three patients with different clinical features had a definite clinical diagnosis of LCA. Patient 1 showed pale disc, attenuated vessels aroud the optic disc and the salt-and-pepper appearance of the retina, had the homozygous c.744.745insT (p.249, L>Ffs4) mutation inSPATA7. Patient 2 showed optic disc pallor and attenuated retinal vessels, had the heterozygous c.535G>A, p.A179T mutation inWFS1. Patient 3 showed pale disc, atrophic macular and retinal and choroidal degeneration, had the heterozygous mutation in CRB1, RPGRIP1, SPATA7. Conclusion LCA has characteristics of genetic heterogeneity and clinical and phenotypic diversity.

Citation： ZHOU Qi, LI Ziyuan, LU Fang. Clinical features and genetic study of three patients with leber congenital amaurosis. West China Medical Journal, 2018, 33(11): 1359-1366. doi: 10.7507/1002-0179.201809128 Copy

1.	Wang H, Wang X, Zou X, et al. Comprehensive molecular diagnosis of a large Chinese Leber congenital amaurosis cohort. Invest Ophthalmol Vis Sci, 2015, 56(6): 3642-3655.
2.	Leber T. Retinitis pigmentosa und angeborene amaurose. Albrecht von Graefes Arch Ophthal, 1869, 15(3): 1-25.
3.	Mayer AK, Mahajnah M, Zobor D, et al. Novel homozygous large deletion including the 5’part of the SPATA7 gene in a consanguineous Israeli Muslim Arab family. Mol Vis, 2015, 21: 306-315.
4.	Galvin JA, Fishman GA, Stone EM, et al. Clinical phenotypes in carriers of Leber congenital amaurosis mutations. Ophthalmology, 2005, 112(2): 349-356.
5.	Weleber RG, Francis PJ, Trzupek KM, et al. Leber congenital amaurosis. GeneReviews®. (2004-07-07)［2013-05-02］. https://www.ncbi.nlm.nih.gov/books/NBK1298/.
6.	den Hollander AI, Roepman R, Koenekoop RK, et al. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res, 2008, 27(4): 391-419.
7.	Wang P, Guo X, Zhang Q. Further evidence of autosomal-dominant Leber congenital amaurosis caused by heterozygous CRX mutation. Graefes Arch Clin Exp Ophthalmo, 2007, 245(9): 1401-1402.
8.	Hosono K, Harada Y, Kurata K, et al. Novel GUCY2D gene mutations in Japanese male twins with Leber congenital amaurosis. J Ophthalmol, 2015: 693468.
9.	Katagiri S, Hayashi T, Kondo M, et al. RPE65 mutations in two Japanese families with Leber congenital amaurosis. Ophthalmic Genet, 2016, 37(2): 161-169.
10.	Perrault I, Hanein S, Gerard X, et al. Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat, 2010, 31(3): E1241-E1250.
11.	Bellingham J, Davidson AE, Aboshiha J, et al. Investigation of aberrant splicing induced by AIPL1 variations as a cause of Leber congenital amaurosis. Invest Ophthalmol Vis Sci, 2015, 56(13): 7784-7793.
12.	Corton M, Avila-Fernandez A, Vallespín E, et al. Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population. Ophthalmology, 2014, 121(1): 399-407.
13.	Koenekoop RK. RPGRIP1 is mutated in Leber congenital amaurosis: a mini-review. Ophthalmic Genet, 2005, 26(4): 175-179.
14.	Nichols LL, Alur RP, Boobalan E, et al. Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL. Hum Mutat, 2010, 31(6): E1472-E1483.
15.	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. Eur J Ophthalmol, 2016, 26(1): 78-84.
16.	Hedergott A, Volk AE, Herkenrath P, et al. Clinical and genetic findings in a family with NMNAT1-associated Leber congenital amaurosis: case report and review of the literature. Graefes Arch Clin Exp Ophthalmol, 2015, 253(12): 2239-2246.
17.	Friedman JS, Chang B, Kannabiran C, et al. Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet, 2006, 79(6): 1059-1070.
18.	Sodi A, Caputo R, Passerini I, et al. Novel RDH12 sequence variations in Leber congenital amaurosis. J AAPOS, 2010, 14(4): 349-351.
19.	Sénéchal A, Humbert G, Surget MO, et al. Screening genes of the retinoid metabolism: novel LRAT mutation in Leber congenital amaurosis. Am J Ophthalmol, 2006, 142(4): 702-704.
20.	Guo Y, Prokudin I, Yu C, et al. Advantage of whole exome sequencing over Allele-specific and targeted segment sequencing in detection of novel TULP1 mutation in Leber congenital amaurosis. Ophthalmic Genet, 2015, 36(4): 333-338.
21.	Pattnaik BR, Shahi PK, Marino MJ, et al. A novel KCNJ13 nonsense mutation and loss of Kir7.1 channel function causes Leber congenital amaurosis (LCA16). Hum Mutat, 2015, 36(7): 720-727.
22.	Stone EM, Cideciyan AV, Aleman TS, et al. Variations in NPHP5 in patients with nonsyndromic Leber congenital amaurosis and senior-loken syndrome. Arch Ophthalmol, 2011, 129(1): 81-87.
23.	Estrada-Cuzcano A, Koenekoop RK, Coppieters F, et al. IQCB1 mutations in patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci, 2011, 52(2): 834-839.
24.	Li L, Xiao X, Li S, et al. Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis. PLoS One, 2011, 6(5): e19458.
25.	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 Med Genet, 2013, 50(10): 674-688.
26.	Mackay DS, Ocaka LA, Borman AD, et al. Screening of SPATA7 in patients with Leber congenital amaurosis and severe childhood-onset retinal dystrophy reveals disease-causing mutations. Invest Ophthalmol Vis Sci, 2011, 52(6): 3032-3038.
27.	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. Int J Ophthalmol, 2016, 9(9): 1260-1264.
28.	Inoue H, Tanizawa Y, Wasson J, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet, 1998, 20(2): 143-148.
29.	Kawano J, Tanizawa Y, Shinoda K. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. J Comp Neurol, 2008, 510(1): 1-23.
30.	Hofmann S, Philbrook C, Gerbitz KD, et al. Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum Mol Genet, 2003, 12(16): 2003-2012.
31.	Bujakowska K, Audo I, Mohand-Saïd S, et al. CRB1 mutations in inherited retinal dystrophies. Hum Mutat, 2012, 33(2): 306-315.
32.	Hasan SM, Azmeh A, Mostafa O, et al. Coat’s like vasculopathy in Leber congenital amaurosis secondary to homozygous mutations in CRB1: a case report and discussion of the management options. BMC Res Notes, 2016, 9: 91.
33.	Pawlyk BS, Bulgakov OV, Liu X, et al. Replacement gene therapy with a humanRPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis. Hum Gene Ther, 2010, 21(8): 993-1004.
34.	Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat, 2004, 23(4): 306-317.
35.	Galvin JA, Fishman GA, Stone EM, et al. Evaluation of genotype-phenotype associations in Leber congenital amaurosis. Retina, 2005, 25(7): 919-929.
36.	Yzer S, Leroy BP, De Baere E, et al. Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci, 2006, 47(3): 1167-1176.
37.	Yzer S, Hollander AI, Lopez I, et al. Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290. Mol Vis, 2012, 18: 412-425.
38.	Gradstein L, Zolotushko J, Sergeev YV, et al. Novel GUCY2D mutation causes phenotypic variability of Leber congenital amaurosis in a large kindred. BMC Med Genet, 2016, 17(1): 52.
39.	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. PLoS One, 2012, 7(3): e32330.
40.	Hosch J, Lorenz B, Stieger K. RPGR: role in the photoreceptor cilium, human retinal disease, and gene therapy. Ophthalmic Genet, 2011, 32(1): 1-11.
41.	Lorenz B, Gyürüs P, Preising M, et al. Early-onset severe rod-cone dystrophy in young children with RPE65 mutations. Invest Ophthalmol Vis Sci, 2000, 41(9): 2735-2742.
42.	Drivas TG, Holzbaur EL, Bennett J. Disruption of CEP290 microtubule/membrane-binding domains causes retinal degeneration. J Clin Invest, 1994, 123(10): 4525-4539.
43.	Perrault I, Delphin N, Hanein S, et al. Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat, 2007, 28(4): 416.
44.	Koenekoop RK, Wang H, Majewski J, et al. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat Genet, 2012, 44(9): 1035-1039.
45.	Hufnagel RB, Ahmed ZM, Corrêa ZM, et al. Gene therapy for Leber congenital amaurosis: advances and future directions. Graefes Arch Clin Exp Ophthalmol, 2012, 250(8): 1117-1128.

1. Wang H, Wang X, Zou X, et al. Comprehensive molecular diagnosis of a large Chinese Leber congenital amaurosis cohort. Invest Ophthalmol Vis Sci, 2015, 56(6): 3642-3655.
2. Leber T. Retinitis pigmentosa und angeborene amaurose. Albrecht von Graefes Arch Ophthal, 1869, 15(3): 1-25.
3. Mayer AK, Mahajnah M, Zobor D, et al. Novel homozygous large deletion including the 5’part of the SPATA7 gene in a consanguineous Israeli Muslim Arab family. Mol Vis, 2015, 21: 306-315.
4. Galvin JA, Fishman GA, Stone EM, et al. Clinical phenotypes in carriers of Leber congenital amaurosis mutations. Ophthalmology, 2005, 112(2): 349-356.
5. Weleber RG, Francis PJ, Trzupek KM, et al. Leber congenital amaurosis. GeneReviews®. (2004-07-07)［2013-05-02］. https://www.ncbi.nlm.nih.gov/books/NBK1298/.
6. den Hollander AI, Roepman R, Koenekoop RK, et al. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res, 2008, 27(4): 391-419.
7. Wang P, Guo X, Zhang Q. Further evidence of autosomal-dominant Leber congenital amaurosis caused by heterozygous CRX mutation. Graefes Arch Clin Exp Ophthalmo, 2007, 245(9): 1401-1402.
8. Hosono K, Harada Y, Kurata K, et al. Novel GUCY2D gene mutations in Japanese male twins with Leber congenital amaurosis. J Ophthalmol, 2015: 693468.
9. Katagiri S, Hayashi T, Kondo M, et al. RPE65 mutations in two Japanese families with Leber congenital amaurosis. Ophthalmic Genet, 2016, 37(2): 161-169.
10. Perrault I, Hanein S, Gerard X, et al. Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat, 2010, 31(3): E1241-E1250.
11. Bellingham J, Davidson AE, Aboshiha J, et al. Investigation of aberrant splicing induced by AIPL1 variations as a cause of Leber congenital amaurosis. Invest Ophthalmol Vis Sci, 2015, 56(13): 7784-7793.
12. Corton M, Avila-Fernandez A, Vallespín E, et al. Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population. Ophthalmology, 2014, 121(1): 399-407.
13. Koenekoop RK. RPGRIP1 is mutated in Leber congenital amaurosis: a mini-review. Ophthalmic Genet, 2005, 26(4): 175-179.
14. Nichols LL, Alur RP, Boobalan E, et al. Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL. Hum Mutat, 2010, 31(6): E1472-E1483.
15. 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. Eur J Ophthalmol, 2016, 26(1): 78-84.
16. Hedergott A, Volk AE, Herkenrath P, et al. Clinical and genetic findings in a family with NMNAT1-associated Leber congenital amaurosis: case report and review of the literature. Graefes Arch Clin Exp Ophthalmol, 2015, 253(12): 2239-2246.
17. Friedman JS, Chang B, Kannabiran C, et al. Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet, 2006, 79(6): 1059-1070.
18. Sodi A, Caputo R, Passerini I, et al. Novel RDH12 sequence variations in Leber congenital amaurosis. J AAPOS, 2010, 14(4): 349-351.
19. Sénéchal A, Humbert G, Surget MO, et al. Screening genes of the retinoid metabolism: novel LRAT mutation in Leber congenital amaurosis. Am J Ophthalmol, 2006, 142(4): 702-704.
20. Guo Y, Prokudin I, Yu C, et al. Advantage of whole exome sequencing over Allele-specific and targeted segment sequencing in detection of novel TULP1 mutation in Leber congenital amaurosis. Ophthalmic Genet, 2015, 36(4): 333-338.
21. Pattnaik BR, Shahi PK, Marino MJ, et al. A novel KCNJ13 nonsense mutation and loss of Kir7.1 channel function causes Leber congenital amaurosis (LCA16). Hum Mutat, 2015, 36(7): 720-727.
22. Stone EM, Cideciyan AV, Aleman TS, et al. Variations in NPHP5 in patients with nonsyndromic Leber congenital amaurosis and senior-loken syndrome. Arch Ophthalmol, 2011, 129(1): 81-87.
23. Estrada-Cuzcano A, Koenekoop RK, Coppieters F, et al. IQCB1 mutations in patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci, 2011, 52(2): 834-839.
24. Li L, Xiao X, Li S, et al. Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis. PLoS One, 2011, 6(5): e19458.
25. 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 Med Genet, 2013, 50(10): 674-688.
26. Mackay DS, Ocaka LA, Borman AD, et al. Screening of SPATA7 in patients with Leber congenital amaurosis and severe childhood-onset retinal dystrophy reveals disease-causing mutations. Invest Ophthalmol Vis Sci, 2011, 52(6): 3032-3038.
27. 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. Int J Ophthalmol, 2016, 9(9): 1260-1264.
28. Inoue H, Tanizawa Y, Wasson J, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet, 1998, 20(2): 143-148.
29. Kawano J, Tanizawa Y, Shinoda K. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. J Comp Neurol, 2008, 510(1): 1-23.
30. Hofmann S, Philbrook C, Gerbitz KD, et al. Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum Mol Genet, 2003, 12(16): 2003-2012.
31. Bujakowska K, Audo I, Mohand-Saïd S, et al. CRB1 mutations in inherited retinal dystrophies. Hum Mutat, 2012, 33(2): 306-315.
32. Hasan SM, Azmeh A, Mostafa O, et al. Coat’s like vasculopathy in Leber congenital amaurosis secondary to homozygous mutations in CRB1: a case report and discussion of the management options. BMC Res Notes, 2016, 9: 91.
33. Pawlyk BS, Bulgakov OV, Liu X, et al. Replacement gene therapy with a humanRPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis. Hum Gene Ther, 2010, 21(8): 993-1004.
34. Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat, 2004, 23(4): 306-317.
35. Galvin JA, Fishman GA, Stone EM, et al. Evaluation of genotype-phenotype associations in Leber congenital amaurosis. Retina, 2005, 25(7): 919-929.
36. Yzer S, Leroy BP, De Baere E, et al. Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci, 2006, 47(3): 1167-1176.
37. Yzer S, Hollander AI, Lopez I, et al. Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290. Mol Vis, 2012, 18: 412-425.
38. Gradstein L, Zolotushko J, Sergeev YV, et al. Novel GUCY2D mutation causes phenotypic variability of Leber congenital amaurosis in a large kindred. BMC Med Genet, 2016, 17(1): 52.
39. 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. PLoS One, 2012, 7(3): e32330.
40. Hosch J, Lorenz B, Stieger K. RPGR: role in the photoreceptor cilium, human retinal disease, and gene therapy. Ophthalmic Genet, 2011, 32(1): 1-11.
41. Lorenz B, Gyürüs P, Preising M, et al. Early-onset severe rod-cone dystrophy in young children with RPE65 mutations. Invest Ophthalmol Vis Sci, 2000, 41(9): 2735-2742.
42. Drivas TG, Holzbaur EL, Bennett J. Disruption of CEP290 microtubule/membrane-binding domains causes retinal degeneration. J Clin Invest, 1994, 123(10): 4525-4539.
43. Perrault I, Delphin N, Hanein S, et al. Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat, 2007, 28(4): 416.
44. Koenekoop RK, Wang H, Majewski J, et al. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat Genet, 2012, 44(9): 1035-1039.
45. Hufnagel RB, Ahmed ZM, Corrêa ZM, et al. Gene therapy for Leber congenital amaurosis: advances and future directions. Graefes Arch Clin Exp Ophthalmol, 2012, 250(8): 1117-1128.

West China Medical Journal

Clinical features and genetic study of three patients with leber congenital amaurosis

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content