切换至 "中华医学电子期刊资源库"

中华眼科医学杂志(电子版) ›› 2019, Vol. 09 ›› Issue (05) : 292 -297. doi: 10.3877/cma.j.issn.2095-2007.2019.05.005

论著

一个FBN1基因突变的先天性单纯性晶状体异位家系的分析
叶晔1, 刘欣华1, 孙良南1, 蔡嘉敏1, 赵军1,()   
  1. 1. 518040 深圳大学眼视光学院 深圳市眼科医院 深圳市眼病研究所
  • 收稿日期:2019-09-12 出版日期:2019-10-28
  • 通信作者: 赵军
  • 基金资助:
    广东省自然科学基金(S2013010013464); 深圳市科技计划项目(GJHZ20180420180937076); 深圳市医疗卫生三名工程项目(SZSM201812090)

Analysis of a novel mutation of FBN1 gene in a Chinese family with congenital isolated ectopia lentis

Ye Ye1, Xinhua Liu1, Liangnan Sun1, Jiamin Cai1, Jun Zhao1,()   

  1. 1. School of Ophthalmology & Optometry Affiliated to Shenzhen University, Shenzhen Eye Hospital, Shenzhen Eye Institute, Shenzhen 518040, China
  • Received:2019-09-12 Published:2019-10-28
  • Corresponding author: Jun Zhao
引用本文:

叶晔, 刘欣华, 孙良南, 蔡嘉敏, 赵军. 一个FBN1基因突变的先天性单纯性晶状体异位家系的分析[J/OL]. 中华眼科医学杂志(电子版), 2019, 09(05): 292-297.

Ye Ye, Xinhua Liu, Liangnan Sun, Jiamin Cai, Jun Zhao. Analysis of a novel mutation of FBN1 gene in a Chinese family with congenital isolated ectopia lentis[J/OL]. Chinese Journal of Ophthalmologic Medicine(Electronic Edition), 2019, 09(05): 292-297.

目的

分析一个晶状体异位家系的临床特征及致病基因,并探讨基因突变与其临床表型间的关系。

方法

2018年8月收集晶状体异位家系的临床资料,绘制家系系谱图。采集家系成员的外周静脉血,提取基因组脱氧核糖核酸,应用靶向基因测序方法初步筛选该家系候选突变基因,采用Sanger测序验证和家系共分离分析,确定该家系的致病基因及其突变位点。

结果

该家系成员共有两代4人。其中,先证者Ⅱ1及其患病母亲分别于6岁及17岁时确诊为双眼晶状体异位,无骨骼系统及心血管系统等异常;先证者Ⅱ1及其患病母亲携带FBN1基因c.1600T>A (p.C534S)杂合突变,生物信息学分析提示具有高致病性,符合家系共分离特征。

结论

该家系符合先天性单纯性晶状体异位疾病特征;FBN1基因c.1600T>A (p.C534S)是该家系的致病突变,为常染色体显性遗传;该位点突变导致第534号氨基酸由半胱氨酸变异为丝氨酸,此为人群中的首次报道。

Objective

The aim of this study was to analyse the clinical characteristics and pathogenic gene of a family with ectopia lentis, and to discuss the genotype-phenotype correlations.

Methods

Clinical data was collected from a Chinese family with ectopia lentis in August, 2018 and the pedigree chart was drawn. Pathogenic mutation was initially identified from the genomic DNA of peripheral venous blood by targeted gene sequencing (or gene-panel sequencing). All variants were then verified by Sanger sequencing and checked their co-segregation with the phenotypes in the family.

Results

The pedigree consisted of 2 generations and 4 family members. The proband (Ⅱ1) and his mother were diagnosed as ectopia lentis at the age of 6- and 17-years-old, respectively, while the abnormality of skeletal system and cardiovascular system was not found. These patients with ectopia lentis carried a mutation c. 1600T>A (p.C534S) in the FBN1 gene, which was predicted to be highly harmful by bioinformatics analysis and in accord with the characteristics of family segregation.

Conclusions

The patients were diagnosed ascongenital isolated ectopia lentis in the pedigree.The FBN1 c. 1600T>A (p.C534S) mutation was the pathogenic mutation of this family, which was autosomal dominant inheritance in the family. To the best of our knowledge, it was the first report of the mutation from cysteine to serine of the FBN1 gene for ectopia lentis in humans.

图1 家系系谱图 □示正常男性;●示患病女性;■示患病男性;↗示先证者
图4  FBN1基因Sanger法测序的部分结果图 图4A、B分别为正常家系成员Ⅰ1及Ⅱ2的FBN1基因13号外显子第1600号核苷酸均未发现突变(红箭头);图4C、D分别为先证者Ⅱ1及Ⅰ2FBN1基因c.1600T>A错义突变(红箭头)
表1 家系患病者的部分临床特征
[1]
Greene VB, Stoetzel C, Pelletier V, et al. Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis[J]. Ophthalmic Genet, 201031(1): 47-51.
[2]
Sadiq MA, Vanderveen D. Genetics of ectopia lentis[J]. Semin Ophthalmol, 201328(5-6): 313-320.
[3]
Sakai LY, Keene DR, Renard M, et al. FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders[J]. Gene, 2016591(1): 279-291.
[4]
Faivre L, Collod-Beroud G, Loeys BL, et al. Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study[J]. Am J Hum Genet, 200781(3): 454-466.
[5]
Lönnqvist L, Child A, Kainulainen K, et al. A novel mutation of the fibrillin gene causing ectopia lentis[J]. Genomics, 199419(3): 573-576.
[6]
Aragon-Martin JA, Ahnood D, Charteris DG, et al. Role of ADAMTSL4 mutations in FBN1 mutation-negative ectopia lentis patients[J]. Hum Mutat, 2010, 31(8): E1622-1631.
[7]
中国眼遗传病诊疗小组,中国眼科遗传联盟. 眼遗传病基因诊断方法专家共识[J]. 中华实验眼科杂志201836(7): 481-488.
[8]
Shendure J, Porreca GJ, Reppas NB, et al. Accurate multiplex polony sequencing of an evolved bacterial genome[J]. Science, 2005, 309(5741): 1728-1732.
[9]
McLean JS, Lasken RS. Single cell genomics of bacterial pathogens: outlook for infectious disease research[J]. Genome Med, 20146(11): 108.
[10]
Heather JM, Chain B. The sequence of sequencers: The history of sequencing DNA[J]. Genomics, 2016, 107(1): 1-8.
[11]
Adams DR, Eng CM. Next-generation sequencing to diagnose suspected genetic disorders[J]. N Engl J Med, 2018, 379(14): 1353-1362.
[12]
Rehm HL. Disease-targeted sequencing: a cornerstone in the clinic[J]. Nat Rev Genet, 201314(4): 295-300.
[13]
Retterer K, Juusola J, Cho MT, et al. Clinical application of whole-exome sequencing across clinical indications[J]. Genet Med, 201618(7): 696-704.
[14]
Tan TY, Dillon OJ, Stark Z, et al. Diagnostic impact and cost-effectiveness of whole-exome sequencing for ambulant children with suspected monogenic conditions[J]. JAMA Pediatr, 2017171(9): 855-862.
[15]
Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders[J]. N Engl J Med, 2013369(16): 1502-1511.
[16]
Neuhann TM, Stegerer A, Riess A, et al. ADAMTSL4-associated isolated ectopia lentis: further patients, novel mutations and a detailed phenotype description[J]. Am J Med Genet A, 2015167A(10): 2376-2381.
[17]
Chandra A, Aragon-Martin JA, Hughes K, et al. A genotype-phenotype comparison of ADAMTSL4 and FBN1 in isolated ectopia lentis[J]. Invest Ophthalmol Vis Sci, 201253(8): 4889-4896.
[18]
Jaureguy BM, Hall JG. Isolated congenital ectopia lentis with autosomal dominant inheritance[J]. Clin Genet, 197915(1): 97-109.
[19]
Edwards MJ, Challinor CJ, Colley PW, et al. Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1[J]. Am J Med Genet, 199453(1): 65-71.
[20]
Fuchs J, Rosenberg T. Congenital ectopia lentis. A Danish national survey[J]. Acta Ophthalmol Scand, 199876(1): 20-26.
[21]
Li J, Jia X, Li S, et al. Mutation survey of candidate genes in 40 Chinese patients with congenital ectopia lentis[J]. Mol Vis, 201420: 1017-1024.
[22]
Traboulsi EI, Whittum-Hudson JA, Mir SH, et al. Microfibril abnormalities of the lens capsule in patients with Marfan syndrome and ectopia lentis[J]. Ophthalmic Genet, 2000, 21(1): 9-15.
[23]
Nelson L. Ectopia lentis in childhood[J]. J Pediatr Ophthalmol Strabismus, 200845(1): 12.
[24]
Neuhann TM. Hereditary ectopia lentis[J]. Klin Monbl Augenheilkd, 2015232(3): 259-265.
[25]
Neely DE, Plager DA. Management of ectopia lentis in children[J]. Ophthalmol Clin North Am, 200114(3): 493-499.
[26]
Lam DS, Young AL, Leung AT, et al. Scleral fixation of a capsular tension ring for severe ectopia lentis[J]. J Cataract Refract Surg, 200026(4): 609-612.
[27]
Wagoner MD, Cox TA, Ariyasu RG, et al. Intraocular lens implantation in the absence of capsular support: a report by the American Academy of Ophthalmology[J]. Ophthalmology, 2003110(4): 840-859.
[28]
Johnston RL, Charteris DG, Horgan SE, et al. Combined pars plana vitrectomy and sutured posterior chamber implant[J]. Arch Ophthalmol, 2000118(7): 905-910.
[29]
Yang YF, Bunce C, Dart JK, et al. Scleral-fixated posterior chamber intraocular lenses in non-vitrectomized eyes[J]. Eye (Lond), 200620(1): 64-70.
[30]
Cleary C, Lanigan B, O′Keeffe M. Artisan iris-claw lenses for the correction of aphakia in children following lensectomy for ectopia lentis[J]. Br J Ophthalmol, 201296(3): 419-421.
[31]
Hsing YE, Lee GA. Retropupillary iris claw intraocular lens for aphakia[J]. Aus N Zeal J Ophthalmol, 201240(9): 849-854.
[32]
夏文佼,巩雪,肖伟. 先天性晶状体脱位致病基因研究进展[J]. 国际眼科杂志201616(4): 651-653.
[33]
Biggin A, Holman K, Brett M, et al. Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy[J]. Hum Mutat, 200423(1): 99.
[34]
Cain SA, Morgan A, Sherratt MJ, et al. Proteomic analysis of fibrillin-rich microfibrils[J]. Proteomics, 20066(1): 111-122.
[35]
Mir S, Wheatley HM, Hussels IE, et al. A comparative histologic study of the fibrillin microfibrillar system in the lens capsule of normal subjects and subjects with Marfan syndrome[J]. Invest Ophthalmol Vis Sci, 199839(1): 84-93.
[36]
Milewicz DM, Urbán Z, Boyd C. Genetic disorders of the elastic fiber system[J]. Matrix Biol, 200019(6): 471-480.
[37]
Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene[J]. Nature, 1991352(6333): 337-339.
[38]
Cañadas V, Vilacosta I, Bruna I, et al. Marfan syndrome. Part 1: pathophysiology and diagnosis[J]. Nat Rev Cardiol, 2010, 7(5): 256-265.
[39]
Schrijver I, Liu W, Brenn T, et al. Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes[J]. Am J Hum Genet, 199965(4): 1007-1020.
[40]
Zadeh N, Bernstein JA, Niemi AK, et al. Ectopia lentis as the presenting and primary feature in Marfan syndrome[J]. Am J Med Genet A, 2011155A(11): 2661-2668.
[41]
Arbustini E, Grasso M, Ansaldi S, et al. Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies[J]. Hum Mutat, 2005, 26(5): 494.
[42]
Adès LC, Holman KJ, Brett MS, et al. Ectopia lentis phenotypes and the FBN1 gene[J]. Am J Med Genet A, 2004126A(3): 284-289.
[43]
Comeglio P, Johnson P, Arno G, et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations[J]. Hum Mutat, 200728(9): 928.
[44]
Collod-Béroud G, Le Bourdelles S, Ades L, et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database[J]. Hum Mutat, 200322(3): 199-208.
[45]
Boileau C. The FBN1 gene mutations database[EB/OL] (2019-03-20)[2019-07-13]

URL    
[1] 戴飞, 赵博文, 潘美, 彭晓慧, 陈冉, 田园诗, 狄敏. 胎儿心脏超声定量多参数对主动脉缩窄胎儿心脏结构及功能的诊断价值[J/OL]. 中华医学超声杂志(电子版), 2024, 21(10): 950-958.
[2] 杨忠, 时敬业, 邓学东, 姜纬, 殷林亮, 潘琦, 梁泓, 马建芳, 王珍奇, 张俊, 董姗姗. 产前超声在胎儿22q11.2 微缺失综合征中的应用价值[J/OL]. 中华医学超声杂志(电子版), 2024, 21(09): 852-858.
[3] 张商迪, 赵博文, 潘美, 彭晓慧, 陈冉, 毛彦恺, 陈阳, 袁华, 陈燕. 中晚孕期胎儿心房内径定量评估心房比例失调胎儿心脏畸形的价值[J/OL]. 中华医学超声杂志(电子版), 2024, 21(08): 785-793.
[4] 张盼盼, 赵博文, 潘美, 彭晓慧, 陈冉, 田园诗, 林仙方, 惠姗姗, 沈婷婷. 胎儿左心房后间隙指数在胎儿肺动脉瓣缺如综合征中的应用价值[J/OL]. 中华医学超声杂志(电子版), 2024, 21(04): 391-398.
[5] 许银峰, 盛璞义, 余世明, 张阳春. 偏心性髋臼旋转截骨术治疗发育性髋关节发育不良[J/OL]. 中华关节外科杂志(电子版), 2024, 18(05): 568-574.
[6] 王濛, 王華麟, 王鉴, 孙锟. 先天性心脏病宫内诊疗现状与展望[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(05): 481-485.
[7] 王雅楠, 刘丹, 曹正浓, 贾慧敏. 儿童迟发性先天性膈疝患儿的临床诊治特点分析[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(04): 410-419.
[8] 谭娟, 谭建新, 邵彬彬, 王艳, 许争峰. 胎儿单基因遗传病无创产前检测的研究现状[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(03): 245-250.
[9] 梅娟, 陶旭炜. 弥散性血管内凝血为首发表现先天性肝内门体静脉分流新生儿2例并文献复习[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(03): 322-330.
[10] 张艳兰, 徐琳, 王彩英, 杨洪玲, 庞琳. 56例先天性梅毒新生儿的临床特征及预后[J/OL]. 中华实验和临床感染病杂志(电子版), 2024, 18(03): 163-169.
[11] 吕小飞, 赵舸. 皮下预置盲襻型胆肠吻合术治疗成人先天性胆管扩张症[J/OL]. 中华普通外科学文献(电子版), 2024, 18(04): 258-261.
[12] 郑伟军, 方一凡, 吴典明, 王翔, 陈飞, 刘明坤. 先天性肠旋转不良诊治分析:单中心10年经验总结[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(03): 338-341.
[13] 曾纪晓, 徐晓钢, 王欣星, 刘斐, 兰梦龙, 陶波圆, 梁子建, 叶志华, 罗媛圆. 达芬奇机器人辅助Swenson-like巨结肠根治术[J/OL]. 中华腔镜外科杂志(电子版), 2024, 17(04): 239-243.
[14] 王双兴, 吴永杰, 孟兵, 张宏涛, 刁美, 张辉. 微创切口联合腹腔镜同期治疗先天性心脏病合并心外畸形[J/OL]. 中华腔镜外科杂志(电子版), 2024, 17(04): 244-249.
[15] 冯勇, 夏仁鹏, 邹婵娟, 许光, 李碧香, 李波, 周崇高. 完全腹腔镜与传统腹腔镜手术治疗婴儿胆总管囊肿的对比研究[J/OL]. 中华腔镜外科杂志(电子版), 2024, 17(02): 90-94.
阅读次数
全文


摘要