表型温和的1型神经纤维瘤病：5个家系基因突变分析

doi:10.35541/cjd.20201263

中华皮肤科杂志 ›› 2022, Vol. 55 ›› Issue (6): 519-522.doi: 10.35541/cjd.20201263

表型温和的1型神经纤维瘤病：5个家系基因突变分析

祝英¹ 郭韫懿¹ 张丹露¹ 郭碧蓉² 孙忠辉¹

¹上海市奉贤区皮肤病防治所皮肤科，上海 201408；²安徽医科大学第三附属医院合肥市第一人民医院皮肤科，合肥 230022

收稿日期:2020-12-31 修回日期:2021-10-31 发布日期:2022-06-02
通讯作者: 孙忠辉；郭碧蓉 E-mail:szhgyy3344@163.com; guobr1983@163.com
作者简介:作者要求在2022年6月前刊出
基金资助:
上海市奉贤区科委社会类科技发展基金项目（奉科20171003）；皮肤病学教育部重点实验室（安徽医科大学）开放课题基金（AY2017-1-017）

Mutation analysis in 5 families with mild phenotypes of neurofibromatosis type 1

Zhu Ying¹, Guo Yunyi¹, Zhang Danlu¹, Guo Birong², Sun Zhonghui¹

¹Department of Dermatology, Fengxian Institute of Dermatosis Prevention and Treatment, Shanghai 201408, China; ²Department of Dermatology, The Third Affiliated Hospital of Anhui Medical University, Hefei First People′s Hospital, Hefei 230022, China

Received:2020-12-31 Revised:2021-10-31 Published:2022-06-02
Contact: Sun Zhonghui; Guo Birong E-mail:szhgyy3344@163.com; guobr1983@163.com
Supported by:
Social Science and Technology Development Fund of Shanghai Fengxian District Science and Technology Commission （Fengke 20171003）; Open Research Fund of Ministry of Education Key Laboratory of Dermatology （Anhui Medical University）（AY2017-1-017）

摘要/Abstract

摘要： 【摘要】目的检测表型温和的1型神经纤维瘤病（NF1）患者的基因突变。方法 2017年6月至2020年6月于上海市奉贤区皮肤病防治所皮肤科门诊收集5例表型温和、仅有皮损的NF1先证者及其家系成员，在家系调查的基础上，观察和记录NF1的临床表型，并利用二代靶向基因测序结合Sanger测序来检测和验证致病突变。结果 5例先证者都仅有皮损（包括咖啡斑、雀斑、神经纤维瘤），无其他系统损害；5个家系先证者共发现5种突变，分别位于NF1基因的不同外显子中，包括1个大片段缺失突变（hg38：chr17：31327199-31335928 del 8 730 bp）、1个剪切突变（c.7970+1G>T）、1个插入突变（c.3011 _3012insTATG，p.N1004fs*）、1个缺失突变（c.1754_1757delTAAC， p.T586Vfs*18）和1个无义突变（c.C503G，p.S168X），前3种是未经报道的新突变。结论在5个先证者表型温和的NF1家系中检测出5种突变，鉴定出3种新突变，丰富了NF1的突变谱。

关键词: 神经纤维瘤病1型, DNA突变分析, 表型

Abstract: 【Abstract】 Objective To detect gene mutations in patients with mild phenotypes of neurofibromatosis type 1 （NF1）. Methods From June 2017 to June 2020, 5 probands with mild phenotypes of NF1 only involving lesions and their family members were collected from Department of Dermatology, Fengxian Institute of Dermatosis Prevention and Treatment in Shanghai. Pedigree investigation was performed to evaluate the clinical phenotypes of NF1. The second-generation targeted gene sequencing combined with Sanger sequencing was performed to detect and verify pathogenic mutations. Results All the 5 probands only presented with skin lesions, including café-au-lait spots, freckles, neurofibromas, without other systemic involvement. A total of 5 mutations were identified in different exons of the NF1 gene in the 5 families, including 1 large-fragment deletion mutation （hg38: chr17:31327199-31335928 del 8 730 bp）, 1 splicing mutation （C.7970+1G>T）, 1 insertion mutation （C.3011_3012insTATG, p.N1004fs*）, 1 deletion mutation （C.1754_1757delTAAC, p.T586Vfs*18）, and 1 nonsense mutation （c.C503G, p.S168X）, and the first 3 above mentioned mutations were unreported novel mutations. Conclusion Five mutations were identified in the 5 families with mild phenotypes of NF1, including 3 novel mutations, which expand the mutational spectrum of NF1.

Key words: Neurofibromatosis 1, DNA mutational analysis, Phenotype

祝英郭韫懿张丹露郭碧蓉孙忠辉. 表型温和的1型神经纤维瘤病：5个家系基因突变分析[J]. 中华皮肤科杂志, 2022,55(6):519-522. doi:10.35541/cjd.20201263

Zhu Ying, Guo Yunyi, Zhang Danlu, Guo Birong, Sun Zhonghui. Mutation analysis in 5 families with mild phenotypes of neurofibromatosis type 1[J]. Chinese Journal of Dermatology, 2022, 55(6): 519-522.doi:10.35541/cjd.20201263

参考文献 19

［1］	Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neuro⁃fibromatosis 1 and neurofibromatosis 2［J］. JAMA, 1997,278（1）:51⁃57.
［2］	Zhang J, Tong H, Fu X, et al. Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype⁃Phenotype Correlations in a Chinese Population［J］. Sci Rep, 2015,5:11291. doi: 10. 1038/srep11291.
［3］	Mautner VF, Kluwe L, Friedrich RE, et al. Clinical characterisation of 29 neurofibromatosis type⁃1 patients with molecularly ascertained 1.4 Mb type⁃1 NF1 deletions［J］. J Med Genet, 2010,47（9）:623⁃630. doi: 10.1136/jmg.2009.075937.
［4］	孙忠辉, 李明, 郭韫懿, 等. 基因检测诊断仅有咖啡色斑表现的儿童Ⅰ型神经纤维瘤病一例［J］. 中华皮肤科杂志, 2013,46（7）:511⁃512. doi: 10.3760/cma.j.issn.0412⁃4030.2013.07.019.
［5］	Nemethova M, Bolcekova A, Ilencikova D, et al. Thirty⁃nine novel neurofibromatosis 1 （NF1） gene mutations identified in Slovak patients［J］. Ann Hum Genet, 2013,77（5）:364⁃379. doi: 10.1111/ahg.12026.
［6］	倪成. 遗传性角化性皮肤病基因型-表型关系研究［D］. 上海: 上海交通大学, 2016.
［7］	Mao B, Chen S, Chen X, et al. Clinical characteristics and spectrum of NF1 mutations in 12 unrelated Chinese families with neurofibromatosis type 1［J］. BMC Med Genet, 2018,19（1）:101. doi: 10.1186/s12881⁃018⁃0615⁃8.
［8］	Corsello G, Antona V, Serra G, et al. Clinical and molecular characterization of 112 single⁃center patients with Neurofibromatosis type 1［J］. Ital J Pediatr, 2018,44（1）:45. doi: 10.1186/s13052⁃018⁃0483⁃z.
［9］	Wimmer K, Yao S, Claes K, et al. Spectrum of single⁃ and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients［J］. Genes Chromosomes Cancer, 2006,45（3）:265⁃276. doi: 10.1002/gcc.20289.
［10］	Zhu L, Zhang Y, Tong H, et al. Clinical and molecular characterization of NF1 patients: single⁃center experience of 32 patients from China［J］. Medicine （Baltimore）, 2016,95（10）:e3043. doi: 10.1097/MD.0000000000003043.
［11］	Orzan F, Stroppi M, Venturin M, et al. Breakpoint characterization of a novel NF1 multiexonic deletion: a case showing expression of the mutated allele［J］. Neurogenetics, 2008,9（2）:95⁃100. doi: 10.1007/s10048⁃007⁃0115⁃z.
［12］	Jang MA, Kim YE, Kim SK, et al. Identification and characterization of NF1 splicing mutations in Korean patients with neurofibromatosis type 1［J］. J Hum Genet, 2016,61（8）:705⁃709. doi: 10.1038/jhg.2016.33.
［13］	Ars E, Serra E, García J, et al. Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1［J］. Hum Mol Genet, 2000,9（2）:237⁃247. doi: 10.1093/hmg/9.2.237.
［14］	Faravelli F, Upadhyaya M, Osborn M, et al. Unusual clustering of brain tumours in a family with NF1 and variable expression of cutaneous features［J］. J Med Genet, 1999,36（12）:893⁃896.
［15］	Trevisson E, Morbidoni V, Forzan M, et al. The Arg1038Gly missense variant in the NF1 gene causes a mild phenotype without neurofibromas［J］. Mol Genet Genomic Med, 2019,7（5）:e616. doi: 10.1002/mgg3.616.
［16］	Koczkowska M, Callens T, Gomes A, et al. Expanding the clinical phenotype of individuals with a 3⁃bp in⁃frame deletion of the NF1 gene （c.2970_2972del）: an update of genotype⁃phenotype correlation［J］. Genet Med, 2019,21（4）:867⁃876. doi: 10.1038/s41436⁃018⁃0269⁃0.
［17］	Rojnueangnit K, Xie J, Gomes A, et al. High incidence of noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.arg1809: genotype⁃phenotype correlation［J］. Hum Mutat, 2015,36（11）:1052⁃1063. doi: 10.1002/humu.22832.
［18］	Guo Y, Zhu Y, Zhang D, et al. Typical Chinese pedigree of autosomal dominant genetic disease: neurofibromatosis type 1 with a novel frame⁃shift mutation［J］. J Dermatol, 2017,44（8）:e188⁃e189. doi: 10.1111/1346⁃8138.13899.
［19］	Griffiths S, Thompson P, Frayling I, et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience［J］. Fam Cancer, 2007, 6（1）:21⁃34. doi: 10.1007/s10689⁃006⁃9001⁃3.

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表型温和的1型神经纤维瘤病：5个家系基因突变分析

Mutation analysis in 5 families with mild phenotypes of neurofibromatosis type 1

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