中华眼底病杂志

中华眼底病杂志

六个白化病家系的致病基因筛查及表型分析

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目的观察分析6个白化病家系的致病基因类型及表型特征。 方法回顾性系列病例研究。6个无血缘关系家系中6例白化病先证者和20名家系成员纳入研究。6例先证者中,临床表型符合眼皮肤白化病(OCA)特征5例,符合眼白化病(OA)特征1例。采集先证者及其家系成员外周静脉血,提取全基因组DNA。运用全外显子组或Sanger测序技术进行致病基因筛查,重点分析白化病相关基因变异并分析其临床特征。 结果测序分析于4个家系中发现6个高致病突变,包括2个常染色体隐性复杂合突变[TYR(c.1037-7T>A,c.925_c.926insC)、OCA2(c.2359G>A,c.587T>C)]和2个X染色体杂合突变[GPR143(c.11C>G)、GPR143(c.333G>A)];其中5个为新发突变。所有突变均由Sanger测序证实,分别代表了OCA1型、OCA2型以及OA1型3种亚型。其中一家系临床表型符合OCA特征,分子遗传学证实为OA1型;其余家系临床诊断与遗传学诊断符合。 结论6个白化病家系中4个家系具有6个高致病基因突变,分别代表OCA1型、OCA2型以及OA1型3种亚型。

ObjectiveTo analyze the pathogenic gene types and phenotypic characteristics of 6 albinism families. Methods A retrospective series of case studies. Six probands of albinism and 20 family members were recruited for this study, 5 probands with clinical manifestations of oculocutaneous albinism (OCA) and 1 proband of ocular albinism (OA). Genomic DNA was extracted from peripheral venous blood which was collected from 6 probands and 20 family members. Genetic variations were screened by whole-exome sequencing or Sanger sequencing and then analyzed the relationship between genotypes and phenotypes. Results Genetic sequencing identified 6 potential pathogenic variants in 4 probands, including 2 compound heterozygous mutations in the 2 genes [TYR (c.1037-7T>A, c.925_c.926insC), OCA2 (c.2359G>A, c.587T>C)] associated with OCA1 and OCA2, and 2 hemizygous mutations in the GPR143[GPR143 (c.11C>G), GPR143 (c.333G>A)] associated with OA1, respectively. In which, 5 were novel mutations and confirmed by Sanger sequencing. One case was accorded with OCA in clinical phenotype, but genetic diagnosis was OA1, the others were agreement between clinical diagnosis and genetic diagnosis. Conclusion There are 4 families with mutations in 6 families, representative of 3 type of albinism (OCA1, OCA2, OA1).

关键词: 白化病,眼皮肤/遗传学; GPR143基因; 杂合子; 突变

Key words: Albinism, oculocutaneous/genetics; GPR143 gene; Heterozygote; Mutation

引用本文: 李杰, 邢亚斯, 栗占荣, 路小楠, 戴淑真. 六个白化病家系的致病基因筛查及表型分析. 中华眼底病杂志, 2018, 34(6): 536-540. doi: 10.3760/cma.j.issn.1005-1015.2018.06.003 复制

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1. 李洪义, 郑辉, 吴维青. 白化病相关综合征的遗传与分子发病机制[J]. 国外医学(皮肤性病学分册), 2004, 30(4): 229-231. DOI:10.3760/cma.j.issn.1673-4173.2004.04.010.Li HY, Zheng H, Wu WQ. Molecular genetic mechanism of syndromic forms of albinism[J]. Int J Dermatol Venereol, 2004, 30(4): 229-231. DOI:10.3760/cma.j.issn.1673-4173.2004.04.010.
2. Martinez-Garcia M, Montoliu L. Albinism in Europe[J]. J Dermatol, 2013, 40(5): 319-324. DOI: 10.1111/1346-8138.12170.
3. Oetting WS, King RA. Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism[J]. Hum Mutat, 1999, 13(2): 99-115. DOI: 10.1002/(SICI)1098-1004(1999)13:2<99::AID-HUMU2>3.0.CO;2-C.
4. 魏海云, 李洪义, 郭向明, 等. 白化病的眼表现及其发生机制[J]. 中国实用眼科杂志, 2005, 23(7): 653-656. DOI: 10.3760/cma.j.issn.1006-4443.2005.07.002.Wei HY, Li HY, Guo XM, et al. The manifestations and mechanism of albinism[J]. Chin J Pract Ophthalmol, 2005, 23(7): 653-656. DOI: 10.3760/cma.j.issn.1006-4443.2005.07.002.
5. 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.
6. Kamaraj B, Purohit R. Mutational analysis of oculocutaneous albinism: a compact review[J/OL]. Biomed Res Int, 2014, 2014:905472[2014-06-29]. https://dx.doi.org/10.1155/2014/905472. DOI: 10.1155/2014/905472.
7. Montoliu L, Gronskov K, Wei AH, et al. Increasing the complexity: new genes and new types of albinism[J]. Pigment Cell Melanoma Res, 2014, 27(1): 11-18. DOI: 10.1111/pcmr.12167.
8. Qiu B, Ma T, Peng C, et al. Identification of five novel variants in chinese oculocutaneous albinism by targeted next-generation sequencing[J]. Genet Test Mol Biomarkers, 2018, 22(4): 252-258. DOI: 10.1089/gtmb.2017.0211.
9. Hutton SM, Spritz RA. Comprehensive analysis of oculocutaneous albinism among non-Hispanic caucasians shows that OCA1 is the most prevalent OCA type[J]. J Invest Dermatol, 2008, 128(10): 2442-2450. DOI: 10.1038/jid.2008.109.
10. King RA, Pietsch J, Fryer JP, et al. Tyrosinase gene mutations in oculocutaneous albinism 1(OCA1): definition of the phenotype[J]. Hum Genet, 2003, 113(6): 502-513. DOI: 10.1007/s00439-003-0998-1.
11. Simeonov DR, Wang X, Wang C, et al. DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics[J]. Hum Mutat, 2013, 34(6): 827-835. DOI: 10.1002/humu.22315.
12. Oetting WS, Gardner JM, Fryer JP, et al. Mutations of the human P gene associated with type Ⅱ oculocutaneous albinism (OCA2): mutations in brief no. 205. online[J]. Hum Mutat, 1998, 12(6): 434. DOI:10.1002/(SICI)1098-1004(1998)12:6<434::AID-HUMU16>3.0.CO;2-7.
13. Lewis RA. Ocular Albinism, X-Linked[M]. Seattle (WA): University of Washington, 1993.
14. Fang S, Guo X, Jia X, et al. Novel GPR143 mutations and clinical characteristics in six Chinese families with X-linked ocular albinism[J]. Mol Vis, 2008, 14: 1974-1982.
15. 房绍华, 贾小云, 黎仕强, 等. 中国人眼白化病1型的临床特点观察[J]. 中华眼底病杂志, 2012, 28(4): 376-379. DOI:10.3760/cma.j.issn.1005-1015.2012.04.015.Fang SH, Jia XY, Li SQ, et al. Clinical characteristics of ocular albinism type 1 in China[J]. Chin J Ocul Fundus Dis, 2012, 28(4): 376-379. DOI: 10.3760/cma.j.issn.1005-1015.2012.04.015.
16. Faugere V, Tuffery-Giraud S, Hamel C, et al. Identification of three novel OA1 gene mutations identified in three families misdiagnosed with congenital nystagmus and carrier status determination by real-time quantitative PCR assay[J]. BMC Genet, 2003, 4: 1.
17. Paavo M, Zhao J, Kim HJ, et al. Mutations in GPR143/OA1 and ABCA4 inform interpretations of short-wavelength and near-infrared fundus autofluorescence[J]. Invest Ophthalmol Vis Sci, 2018, 59(6): 2459-2469. DOI: 10.1167/iovs.18-24213.