Genotype and phenotype of <i>CRB1</i> mutated Leber congenital amaurosis and early-onset retinal atrophy_Chinese Journal of Ocular Fundus Diseases

Authors：

Wang Shiyuan , Zhang Xiang , Peng Jie , Hu Yiqian ,  Zhao Peiquan

Department of Ophthalmology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China;

Corresponding author：

Zhao Peiquan, Email: zhaopeiquan@xinhuamed.com.cn

Keywords：

Leber congenital amaurosis; Early-onset retinal atrophy; CRB1 mutation

DOI：

10.3760/cma.j.cn511434-20200929-00478

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Objective To investigate the relationship between genotype and phenotype in children with CRB1 mutated Leber congenital amaurosis (LCA) and early onset retinal dystrophy (EOSRD).Methods A retrospective clinical study. From January 2013 to December 2019, 10 children with CRB1 mutated LCA/EOSRD were enrolled in the study. The patients were identified as CRB1 mutation by the second generation targeted capture sequencing, Sanger sequencing and the family segregation analysis. All children underwent electroretinogram (ERG) and fundus examination. At the same time, 6 cases were examined by optical coherence tomography (OCT); 1 case was examined by fluorescein fundus angiography (FFA), 7 cases were examined by wide-angle laser scanning ophthalmoscope (UWF SLO).Results There were 6 cases of LCA and 4 cases of EOSRD in 10 patients with CRB1 gene mutations. The average age of first visit was 3.61 years old. The light and dark wave of ERG was flat in 6 cases, and decreased in 4 cases. A total of 19 pathogenic mutations were detected. There were 1 homozygous mutation and 9 compound heterozygous mutations. There were 4, 2 and 1 cases of “copper-coin” like, “salt and pepper” like and “osteocyte” like pigment changes in retina, 1 case of “crystalline pigment” change and 2 cases of macular pigment scar. In 7 cases of UWF SLO examination, different degrees of para-arteriolar pigment epithelium retention (PPRPE) were found in the middle and peripheral fundus. In 6 cases examined by OCT, the outer layer of retina atrophied and the band of ellipsoid disappeared. Symmetrical cystoid macular edema, splitting cystoid macular degeneration and adhesion of epi-macular membrane to optic disc and macular area were found in 1 case, respectively, the retinal structure was rough and thickened, and the fovea became thinner in 3 cases. In FFA examination, 1 case showed uveitis-like changes with late optic disc fluorescein staining, macular fluorescence accumulation, strong fluorescence diffusing along the blood vessels in each quadrant, peripheral PPRPE of “frost-branch” like strong fluorescence.Conclusion The relationship between genotype and phenotype of CRB1 mutation is complex, and PPRPE is a common characteristic change.

Citation： Wang Shiyuan, Zhang Xiang, Peng Jie, Hu Yiqian, Zhao Peiquan. Genotype and phenotype of CRB1 mutated Leber congenital amaurosis and early-onset retinal atrophy. Chinese Journal of Ocular Fundus Diseases, 2021, 37(4): 284-289. doi: 10.3760/cma.j.cn511434-20200929-00478 Copy

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2.	Henderson RH, Mackay DS, Li Z, et al. Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1[J]. Br J Ophthalmol, 2011, 95(6): 811-817. DOI: 10.1136/bjo.2010.186882.
3.	Wang S, Zhang Q, Zhang X, et al. Clinical and genetic characteristics of Leber congenital amaurosis with novel mutations in known genes based on a Chinese eastern coast Han population[J]. Graefe's Arch Clin Exp Ophthalmol, 2016, 254(11): 2227-2238. DOI: 10.1007/s00417-016-3428-5.
4.	Mathijssen IB, Florijn RJ, van den Born LI, et al. Long-term follow-up of patients with retinitis pigmentosa type 12 caused by CRB1 mutations: a severe phenotype with considerable interindividual variability[J]. Retina, 2017, 37(1): 161-172. DOI: 10.1097/IAE.0000000000001127.
5.	Talib M, van Schooneveld MJ, van Genderen MM, et al. Genotypic and phenotypic characteristics of CRB1-associated retinal dystrophies: a long-term follow-up study[J]. Ophthalmology, 2017, 124(6): 884-895. DOI: 10.1016/j.ophtha.2017.01.047.
6.	Mucciolo DP, Murro V, Giorgio D, et al. Long-term follow-up of a CRB1-associated maculopathy[J]. Ophthalmic Genet, 2018, 39(4): 522-525. DOI: 10.1080/13816810.2018.1479431.
7.	Quinn PM, Pellissier LP, Wijnholds J. The CRB1 complex: following the trail of crumbs to a feasible gene therapy strategy[J/OL]. Front Neurosci, 2017, 11: 175[2017-04-05]. https://pubmed.ncbi.nlm.nih.gov/28424578/. DOI: 10.3389/fnins.2017.00175.
8.	Bujakowska K, Audo I, Mohand-Said S, et al. CRB1 mutations in inherited retinal dystrophies[J]. Hum Mutat, 2012, 33(2): 306-315. DOI: 10.1002/humu.21653.
9.	Heckenlively JR. Preserved para-arteriole retinal pigment epithelium (PPRPE) in retinitis pigmentosa[J]. Br J Ophthalmol, 1982, 66(1): 26-30. DOI: 10.1136/bjo.66.1.26.
10.	den Hollander AI, Davis J, van der Velde-Visser SD, et al. CRB1 mutation spectrum in inherited retinal dystrophies[J]. Hum Mutat, 2004, 24(5): 355-369. DOI: 10.1002/humu.20093.
11.	Lotery AJ, Malik A, Shami SA, et al. CRB1 mutations may result in retinitis pigmentosa without para-arteriolar RPE preservation[J]. Ophthalmic Genet, 2001, 22(3): 163-169. DOI: 10.1076/opge.22.3.163.2222.
12.	Vincent A, Ng J, Gerth-Kahlert C, et al. Biallelic mutations in CRB1 underlie autosomal recessive familial foveal retinoschisis[J]. Invest Ophthalmol Vis Sci, 2016, 57(6): 2637-2646. DOI: 10.1167/iovs.15-18281.
13.	Lingao MD, Ganesh A, Karthikeyan AS, et al. Macular cystoid spaces in patients with retinal dystrophy[J]. Ophthalmic Genet, 2016, 37(4): 377-383. DOI: 10.3109/13816810.2015.1101775.
14.	Khan AO, El-Ghrably IA. Overlapping retinal phenotypes in a consanguineous family harboring mutations in CRB1 and RS1[J]. Ophthalmic Genet, 2019, 40(1): 17-21. DOI: 10.1080/13816810.2018.1561906.
15.	Murro V, Mucciolo DP, Sodi A, et al. Retinal capillaritis in a CRB1-associated retinal dystrophy[J]. Ophthalmic Genet, 2017, 38(6): 555-558. DOI: 10.1080/13816810.2017.1281966.
16.	Quinn PM, Mulder AA, Henrique Alves C, et al. Loss of CRB2 in Müller glial cells modifies a CRB1-associated retinitis pigmentosa phenotype into a Leber congenital amaurosis phenotype[J]. Hum Mol Genet, 2019, 28(1): 105-123. DOI: 10.1093/hmg/ddy337.
17.	Tsang SH, Burke T, Oll M, et al. Whole exome sequencing identifies CRB1 defect in an unusual maculopathy phenotype[J]. Ophthalmology, 2014, 121(9): 1773-1782. DOI: 10.1016/j.ophtha.2014.03.010.

1. 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.
2. Henderson RH, Mackay DS, Li Z, et al. Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1[J]. Br J Ophthalmol, 2011, 95(6): 811-817. DOI: 10.1136/bjo.2010.186882.
3. Wang S, Zhang Q, Zhang X, et al. Clinical and genetic characteristics of Leber congenital amaurosis with novel mutations in known genes based on a Chinese eastern coast Han population[J]. Graefe's Arch Clin Exp Ophthalmol, 2016, 254(11): 2227-2238. DOI: 10.1007/s00417-016-3428-5.
4. Mathijssen IB, Florijn RJ, van den Born LI, et al. Long-term follow-up of patients with retinitis pigmentosa type 12 caused by CRB1 mutations: a severe phenotype with considerable interindividual variability[J]. Retina, 2017, 37(1): 161-172. DOI: 10.1097/IAE.0000000000001127.
5. Talib M, van Schooneveld MJ, van Genderen MM, et al. Genotypic and phenotypic characteristics of CRB1-associated retinal dystrophies: a long-term follow-up study[J]. Ophthalmology, 2017, 124(6): 884-895. DOI: 10.1016/j.ophtha.2017.01.047.
6. Mucciolo DP, Murro V, Giorgio D, et al. Long-term follow-up of a CRB1-associated maculopathy[J]. Ophthalmic Genet, 2018, 39(4): 522-525. DOI: 10.1080/13816810.2018.1479431.
7. Quinn PM, Pellissier LP, Wijnholds J. The CRB1 complex: following the trail of crumbs to a feasible gene therapy strategy[J/OL]. Front Neurosci, 2017, 11: 175[2017-04-05]. https://pubmed.ncbi.nlm.nih.gov/28424578/. DOI: 10.3389/fnins.2017.00175.
8. Bujakowska K, Audo I, Mohand-Said S, et al. CRB1 mutations in inherited retinal dystrophies[J]. Hum Mutat, 2012, 33(2): 306-315. DOI: 10.1002/humu.21653.
9. Heckenlively JR. Preserved para-arteriole retinal pigment epithelium (PPRPE) in retinitis pigmentosa[J]. Br J Ophthalmol, 1982, 66(1): 26-30. DOI: 10.1136/bjo.66.1.26.
10. den Hollander AI, Davis J, van der Velde-Visser SD, et al. CRB1 mutation spectrum in inherited retinal dystrophies[J]. Hum Mutat, 2004, 24(5): 355-369. DOI: 10.1002/humu.20093.
11. Lotery AJ, Malik A, Shami SA, et al. CRB1 mutations may result in retinitis pigmentosa without para-arteriolar RPE preservation[J]. Ophthalmic Genet, 2001, 22(3): 163-169. DOI: 10.1076/opge.22.3.163.2222.
12. Vincent A, Ng J, Gerth-Kahlert C, et al. Biallelic mutations in CRB1 underlie autosomal recessive familial foveal retinoschisis[J]. Invest Ophthalmol Vis Sci, 2016, 57(6): 2637-2646. DOI: 10.1167/iovs.15-18281.
13. Lingao MD, Ganesh A, Karthikeyan AS, et al. Macular cystoid spaces in patients with retinal dystrophy[J]. Ophthalmic Genet, 2016, 37(4): 377-383. DOI: 10.3109/13816810.2015.1101775.
14. Khan AO, El-Ghrably IA. Overlapping retinal phenotypes in a consanguineous family harboring mutations in CRB1 and RS1[J]. Ophthalmic Genet, 2019, 40(1): 17-21. DOI: 10.1080/13816810.2018.1561906.
15. Murro V, Mucciolo DP, Sodi A, et al. Retinal capillaritis in a CRB1-associated retinal dystrophy[J]. Ophthalmic Genet, 2017, 38(6): 555-558. DOI: 10.1080/13816810.2017.1281966.
16. Quinn PM, Mulder AA, Henrique Alves C, et al. Loss of CRB2 in Müller glial cells modifies a CRB1-associated retinitis pigmentosa phenotype into a Leber congenital amaurosis phenotype[J]. Hum Mol Genet, 2019, 28(1): 105-123. DOI: 10.1093/hmg/ddy337.
17. Tsang SH, Burke T, Oll M, et al. Whole exome sequencing identifies CRB1 defect in an unusual maculopathy phenotype[J]. Ophthalmology, 2014, 121(9): 1773-1782. DOI: 10.1016/j.ophtha.2014.03.010.

Chinese Journal of Ocular Fundus Diseases

Genotype and phenotype of CRB1 mutated Leber congenital amaurosis and early-onset retinal atrophy

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