Genotype and clinical phenotype analysis in patients with retinitis pigmentosa and cone rod dystrophy_Chinese Journal of Ocular Fundus Diseases

Authors：

Wang Xiaoguang , Liu Haijun , Zhang Shaochi , Qi Xiaolong , Pan Bo , Zhuang Wenjuan ,  Sheng Xunlun

Ningxia Eye Hospital, The Ningxia people’s Hospital of Hui Autonomous Region (The First Affiliated Hospital of Northwest Minzu University), Yinchuan 750002, China;

Corresponding author：

Sheng Xunlun, Email: shengxunlun@163.com

Keywords：

Retinal diseases/genetics; Retinitis pigmentosa/genetics; DNA mutational analysis; Phenotype

DOI：

10.3760/cma.j.issn.1005-1015.2018.06.002

Video：

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Objective To observe the gene mutation and clinical phenotype of patients with retinitis pigmentosa (RP) and cone rod dystrophy (CORD). Methods Thirty-seven patients with RP and 6 patients with CORD and 95 family members were enrolled in the study. The patient’s medical history and family history were collected. All the patients and family members received complete ophthalmic examinations to determine the phenotype, including best corrected visual acuity, slit lamp microscope, indirect ophthalmoscopy, color fundus photography, optical coherence tomography, full-field electroretinogram, and fluorescein fundus angiography. DNA was abstracted from patients and family members. Using target region capture sequencing combined with next-generation sequencing to screen the 232 candidate pathogenic mutations. Polymerase chain reaction and direct sequencing were used to confirm the pathogenic pathogenic mutations and Co-segregation is performed among members in the family to determine pathogenic mutation sites. The relationship between genotype and clinical phenotype of RP and CORD was analyzed. Results Of the 37 patients with RP, 13 were from 6 families, including 4 families with autosomal dominant inheritance, 2 families with autosomal recessive inheritance, and 3 in 6 families were detected pathogenic gene mutations. 24 cases were scattered RP. Six patients with CORD were from four families, all of which were autosomal recessive. Of the 43 patients, 21 patients were detected the pathogenic gene mutation, and the positive rate was 48.8%. Among them, 15 patients with RP were detected 10 pathogenic gene mutations including USH2A, RP1, MYO7A, C8orf37, RPGR, SNRNP200, CRX, PRPF31, C2orf71, IMPDH1, and the clinical phenotype included 10 typical RP, 2 cases of RPSP, 3 cases of Usher syndrome type 2 and 6 cases of CORD patients were all detected pathogenic gene mutations, including 2 cases of ABCA4, 2 mutations of RIMS1 gene, 1 case of CLN3 gene mutation, and 1 case of CRB1 and RPGR double gene mutation. Conclusions RP and CORD are clinically diverse in genotype and clinically phenotypically similar. For patients with early RP and CORD, clinical phenotype combined with genetic analysis is required to determine the diagnosis of RP and CORD.

Citation： Wang Xiaoguang, Liu Haijun, Zhang Shaochi, Qi Xiaolong, Pan Bo, Zhuang Wenjuan, Sheng Xunlun. Genotype and clinical phenotype analysis in patients with retinitis pigmentosa and cone rod dystrophy. Chinese Journal of Ocular Fundus Diseases, 2018, 34(6): 526-535. doi: 10.3760/cma.j.issn.1005-1015.2018.06.002 Copy

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2.	王虹, 王雅坤, 叶东升, 等.误诊弱视的儿童眼病[J]. 中国斜视与小儿眼科杂志, 2010, 18(2): 69-71. DOI: 10.3969/j.issn.1005-328X.2010.02.007.Wang H, Wang YK, Ye DS, et al. Misdignosis amblyopia of children with eye disease[J]. Chinese Journal of Strabismus & Pediatric Ophthalmology, 2010, 18(2): 69-71. DOI: 10.3969/j.issn.1005-328X.2010.02.007.
3.	Heckenlively JR, Martin DA, Rosales TO. Telangiectasia and optic atrophy in cone-rod degenerations[J]. Arch Ophthalmol, 1981, 99(11): 1983-1991.
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6.	熊世红, 赵堪兴, 王立, 等.视网膜色素变性患者视紫红质E341ter基因突变及临床表型分析[J]. 中华眼科杂志, 2002, 38(4): 224-227. DOI: 10.3760/j:issn:0412-4081.2002.04.010.Xiong SH, Zhao KX, Wang L, et al. A novel rhodopsin E341ter mutation in patients with retinitis pigmentosa and corresponding clinical phenotype[J]. Chin J Ophthalmol, 2002, 38(4): 224-227. DOI:10.3760/j:issn:0412-4081.2002.04.010.
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11.	Dai H, Zhang X, Zhao X, et al. Identification of five novel mutations in the long isoform of the USH2A gene in Chinese families with Usher syndrome type Ⅱ[J]. Mol Vis, 2008, 14: 2067-2075.
12.	刘雅妮, 陈雪, 庄文娟.先天性静止性夜盲家系和无色素性视网膜色素变性家系临床表型及突变基因的研究[J]. 宁夏医学杂志, 2017, 39(3): 196-199. DOI: 10.13621/j.1001-5949.2017.03.0196.Liu YN, Chen X, Zhuang WJ. Studies the clinical phenotypes and mutation disease-causing geness of congenital stationary night blindness pedigree and retinitis pigmentosa sine pigmento pedigree[J]. Ningxia Med J, 2017, 39(3): 196-199. DOI: 10.13621/j.1001-5949.2017.03.0196.
13.	Michaelides M, Holder GE, Hunt DM, et al. A detailed study of the phenotype of an autosomal dominant cone-rod dystrophy (CORD7) associated with mutation in the gene for RIM1[J]. Br J Ophthalmol, 2005, 89(2): 198-206.DOI: 10.1136/bjo.2004.050773.
14.	Lewis RA, Shroyer NF, Singh N, et al. Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease[J]. Am J Hum Genet, 1999, 64(2): 422-434.DOI: 10.1086/302251.
15.	Allikmets R. Simple and complex ABCR: genetic predisposition to retinal disease[J]. Am J Hum Genet, 2000, 67(4): 793-799. DOI: 10.1086/303100.
16.	Cremers FP, van de Pol DJ, van Driel M, et al. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR[J]. Hum Mol Genet, 1998, 7(3): 355-362.
17.	Maugeri A, Klevering BJ, Rohrschneider K, et al. Mutations in the ABCA4(ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy[J]. Am J Hum Genet, 2000, 67(4): 960-966. DOI: 10.1086/303079.
18.	Webster AR, Heon E, Lotery AJ, et al. An analysis of allelic variation in the ABCA4 gene[J]. Invest Ophthalmol Vis Sci, 2001, 42(6): 1179-1189.
19.	李自立, 庄文娟, 赵巍, 等.一个X-连锁隐性遗传视网膜色素变性家系的RPGR基因新突变[J]. 中华眼科杂志, 2011, 47(6): 516-520. DOI: 10.3760/cma.j.issn.0412-4081.2011.06.008.Li ZL, Zhuang WJ, Zhao W, et al. Novel RPGR gene mutation in a Chinese family with X-linked recessive retinitis pigmentosa[J]. Chin J Ophthalmol, 2011, 47(6): 516-520. DOI: 10.3760/cma.j.issn.0412-4081.2011.06.008.
20.	Yang Z, Peachey NS, Moshfeghi DM, et al. Mutations in the RPGR gene cause X-linked cone dystrophy[J]. Hum Mol Genet, 2002, 11(5): 605-611.
21.	Thiadens AA, Soerjoesing GG, Florijn RJ, et al. Clinical course of cone dystrophy caused by mutations in the RPGR gene[J]. Graefe’s Arch Clin Exp Ophthalmol, 2011, 249(10): 1527-1535. DOI: 10.1007/s00417-011-1789-3.
22.	Beryozkin A, Zelinger L, Bandah-Rozenfeld D, et al. Mutations in CRB1 are a relatively common cause of autosomal recessive early-onset retinal degeneration in the Israeli and Palestinian populations[J]. Invest Ophthalmol Vis Sci, 2013, 54(3): 2068-2075. DOI: 10.1167/iovs.12-11419.
23.	Papadopoulou Laiou C, Preising MN, Bolz HJ, et al.Genotype-Phenotype Correlations in Patients with CRB1 Mutations[J]. Klin Monbl Augenheilkd, 2017, 234(3): 289-302. DOI: 10.1055/s-0043-103961.
24.	Wang F, Wang H, Tuan HF, et al. Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements[J]. Hum Genet, 2014, 133(3): 331-345. DOI: 10.1007/s00439-013-1381-5.
25.	Schultz ML, Tecedor L, Chang M, et al. Clarifying lysosomal storage diseases[J]. Trends Neurosci, 2011, 34(8): 401-410. DOI: 10.1016/j.tins.2011.05.006.

1. 贾惠莉, 朱小丽, 邓宏伟, 等. 误诊为弱视的常见眼病及临床分析[J]. 中国实用眼科杂志, 2013, 31(6): 800-802. DOI: 10.3760/cma.j.issn.1006-4443.2013.06.039.Jia HL, Zhu XL, Deng HW, et al. The common eye diseases of misdiagnosis amblyopia and clinical analysis[J]. Chin J Pract Ophthalmol, 2013, 31(6): 800-802. DOI: 10.3760/cma.j.issn.1006-4443.2013.06.039.
2. 王虹, 王雅坤, 叶东升, 等.误诊弱视的儿童眼病[J]. 中国斜视与小儿眼科杂志, 2010, 18(2): 69-71. DOI: 10.3969/j.issn.1005-328X.2010.02.007.Wang H, Wang YK, Ye DS, et al. Misdignosis amblyopia of children with eye disease[J]. Chinese Journal of Strabismus & Pediatric Ophthalmology, 2010, 18(2): 69-71. DOI: 10.3969/j.issn.1005-328X.2010.02.007.
3. Heckenlively JR, Martin DA, Rosales TO. Telangiectasia and optic atrophy in cone-rod degenerations[J]. Arch Ophthalmol, 1981, 99(11): 1983-1991.
4. Szlyk JP, Fishman GA, Alexander KR, et al. Clinical subtypes of cone-rod dystrophy[J]. Arch Ophthalmol, 1993, 111(6): 781-788.
5. Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa[J]. Clin Genet, 2013, 84(2): 132-141.DOI: 10.1111/cge.12203.
6. 熊世红, 赵堪兴, 王立, 等.视网膜色素变性患者视紫红质E341ter基因突变及临床表型分析[J]. 中华眼科杂志, 2002, 38(4): 224-227. DOI: 10.3760/j:issn:0412-4081.2002.04.010.Xiong SH, Zhao KX, Wang L, et al. A novel rhodopsin E341ter mutation in patients with retinitis pigmentosa and corresponding clinical phenotype[J]. Chin J Ophthalmol, 2002, 38(4): 224-227. DOI:10.3760/j:issn:0412-4081.2002.04.010.
7. 陈彭, 赵明威, 张承芬.视网膜脉络膜变性类疾病[M]//张承芬.眼底病学.2版.北京: 人民卫生出版社, 2010: 508-547.Chen P, Zhao MW, Zhang CF. Retinal choroidal degeneration disease[M]//Zhang CF. Diseases of ocular fundus. 2nd ed. Beijing: People's Medical Publishing House, 2010: 508-547.
8. Lentz J, Keats B. Usher syndrome type Ⅱ[DB/OL]//Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews^®.Seattle(WA): University of Washington, 1999(2016-07-21)[2018-06-19]. https://www.ncbi.nlm.nih.gov/books/NBK1341/.
9. Oishi M, Oishi A, Gotoh N, et al. Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies[J]. Mol Vis, 2016, 22: 150-160.
10. Xu W, Dai H, Lu T, et al. Seven novel mutations in the long isoform of the USH2A gene in Chinese families with nonsyndromic retinitis pigmentosa and Usher syndrome type Ⅱ[J]. Mol Vis, 2011, 17: 1537-1552.
11. Dai H, Zhang X, Zhao X, et al. Identification of five novel mutations in the long isoform of the USH2A gene in Chinese families with Usher syndrome type Ⅱ[J]. Mol Vis, 2008, 14: 2067-2075.
12. 刘雅妮, 陈雪, 庄文娟.先天性静止性夜盲家系和无色素性视网膜色素变性家系临床表型及突变基因的研究[J]. 宁夏医学杂志, 2017, 39(3): 196-199. DOI: 10.13621/j.1001-5949.2017.03.0196.Liu YN, Chen X, Zhuang WJ. Studies the clinical phenotypes and mutation disease-causing geness of congenital stationary night blindness pedigree and retinitis pigmentosa sine pigmento pedigree[J]. Ningxia Med J, 2017, 39(3): 196-199. DOI: 10.13621/j.1001-5949.2017.03.0196.
13. Michaelides M, Holder GE, Hunt DM, et al. A detailed study of the phenotype of an autosomal dominant cone-rod dystrophy (CORD7) associated with mutation in the gene for RIM1[J]. Br J Ophthalmol, 2005, 89(2): 198-206.DOI: 10.1136/bjo.2004.050773.
14. Lewis RA, Shroyer NF, Singh N, et al. Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease[J]. Am J Hum Genet, 1999, 64(2): 422-434.DOI: 10.1086/302251.
15. Allikmets R. Simple and complex ABCR: genetic predisposition to retinal disease[J]. Am J Hum Genet, 2000, 67(4): 793-799. DOI: 10.1086/303100.
16. Cremers FP, van de Pol DJ, van Driel M, et al. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR[J]. Hum Mol Genet, 1998, 7(3): 355-362.
17. Maugeri A, Klevering BJ, Rohrschneider K, et al. Mutations in the ABCA4(ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy[J]. Am J Hum Genet, 2000, 67(4): 960-966. DOI: 10.1086/303079.
18. Webster AR, Heon E, Lotery AJ, et al. An analysis of allelic variation in the ABCA4 gene[J]. Invest Ophthalmol Vis Sci, 2001, 42(6): 1179-1189.
19. 李自立, 庄文娟, 赵巍, 等.一个X-连锁隐性遗传视网膜色素变性家系的RPGR基因新突变[J]. 中华眼科杂志, 2011, 47(6): 516-520. DOI: 10.3760/cma.j.issn.0412-4081.2011.06.008.Li ZL, Zhuang WJ, Zhao W, et al. Novel RPGR gene mutation in a Chinese family with X-linked recessive retinitis pigmentosa[J]. Chin J Ophthalmol, 2011, 47(6): 516-520. DOI: 10.3760/cma.j.issn.0412-4081.2011.06.008.
20. Yang Z, Peachey NS, Moshfeghi DM, et al. Mutations in the RPGR gene cause X-linked cone dystrophy[J]. Hum Mol Genet, 2002, 11(5): 605-611.
21. Thiadens AA, Soerjoesing GG, Florijn RJ, et al. Clinical course of cone dystrophy caused by mutations in the RPGR gene[J]. Graefe’s Arch Clin Exp Ophthalmol, 2011, 249(10): 1527-1535. DOI: 10.1007/s00417-011-1789-3.
22. Beryozkin A, Zelinger L, Bandah-Rozenfeld D, et al. Mutations in CRB1 are a relatively common cause of autosomal recessive early-onset retinal degeneration in the Israeli and Palestinian populations[J]. Invest Ophthalmol Vis Sci, 2013, 54(3): 2068-2075. DOI: 10.1167/iovs.12-11419.
23. Papadopoulou Laiou C, Preising MN, Bolz HJ, et al.Genotype-Phenotype Correlations in Patients with CRB1 Mutations[J]. Klin Monbl Augenheilkd, 2017, 234(3): 289-302. DOI: 10.1055/s-0043-103961.
24. Wang F, Wang H, Tuan HF, et al. Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements[J]. Hum Genet, 2014, 133(3): 331-345. DOI: 10.1007/s00439-013-1381-5.
25. Schultz ML, Tecedor L, Chang M, et al. Clarifying lysosomal storage diseases[J]. Trends Neurosci, 2011, 34(8): 401-410. DOI: 10.1016/j.tins.2011.05.006.

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