| 64 | 0 | 56 |
| 下载次数 | 被引频次 | 阅读次数 |
目的 以咖啡斑为主要表型的儿童新发现NF1基因的突变及功能分析。方法 回顾分析2019年1月至2023年10月在首都医科大学附属首都儿童医学中心因全身多发咖啡斑（皮损> 6个，直径> 5 mm）就诊，临床高度怀疑儿童1型神经纤维瘤病（NF1）的93例患儿临床资料。采用二代测序法对先证者进行基因检测，并对家系成员进行一代Sanger验证。利用RCSB蛋白质数据库的蛋白质三维结构，探究氨基酸单点突变对蛋白质三维结构产生的影响。结果 共93个家系进行了基因检测，基因检测阳性患儿46.24%(43/93)，其中发现8个位点既往未报道，为新发现的突变。结论 以多发咖啡斑为表现的NF1患儿，其基因检测以NF1基因自发突变为主，主要为无义突变和移码突变；发现8个未报道过的突变位点，这些新发现的突变将为NF1临床诊断及基因检测提供新的依据。
Abstract：Objective To identify NF1 gene variants and evaluate their potential functional impact in children whose principal clinical feature is multiple café-au-lait macules. Methods We retrospectively reviewed 93 children seen at the Capital Center for Children's Health, Capital Medical University from January 2019 to October 2023 for multiple café-au-lait macules(>6 lesions, each >5 mm) and with a high clinical suspicion of neurofibromatosis type 1(NF1). Probands underwent next-generation sequencing; candidate variants were confirmed by Sanger sequencing in family members where available. To assess potential structural consequences of missense substitutions, we examined protein three-dimensional models from the RCSB Protein Data Bank. Results Pathogenic or likely pathogenic NF1 variants were detected in 43 of 93 families(detection rate 46.24%). Eight of the identified variant sites were novel and have not been previously reported. The variant spectrum was dominated by de novo truncating mutations(nonsense and frameshift), consistent with loss-of-function mechanisms. Conclusion Among children presenting mainly with multiple café-au-lait macules, NF1 mutations are frequently de novo and are predominantly truncating variants. The identification of eight novel NF1 mutation sites expands the mutational spectrum and will aid clinical diagnosis and genetic testing for NF1.
[1]Lammert M, Friedman JM, Kluwe L, et al. Prevalence of neuro bromatosis 1 in German children at elementary school enrollment[J].Arch Dermatol, 2005, 141(1):71-74.DOI:10.1001/archderm.141.1.71.
[2]Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome:an international consensus recommendation[J]. Genet Med, 2021, 23(8):1506-1513.DOI:10.1038/s41436-021-01170-5.
[3]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.
[4]Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes:estimates from a UK family genetic register service[J]. Am J Med Genet A, 2010, 152A(2):327-332. DOI:10.1002/ajmg.a.33139.
[5]Yang, H., Yu, Z., Chen, X. et al. Structural insights into TSC complex assembly and GAP activity on Rheb[J]. Nat Commun, 2021, 12(1):339-343. DOI:10.1038/s41467-020-20522-4.
[6]Chaker-Margot M, Werten S, Dunzendorfer-Matt T, et al. Structural basis of activation of the tumor suppressor protein neurofibromin[J].Mol Cell, 2022, 82(7):1288-1296. DOI:10.1016/j.molcel.2022.03.011.
[7]Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2[J]. JAMA, 1997, 278(1):51-57. DOI:10.1001/jama.1997.03550180043031.
[8]DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children[J].Pediatrics, 2000, 105(3):608-614.DOI:10.1542/peds.105.3.608.
[9]Cimino PJ, Gutmann DH. Neurofibromatosis type 1[J]. Handb Clin Neuro, 2018, 148(2):799-811. DOI:10.1016/B978-0-444-64076-5.00051-X.
[10]Solga AC, Toonen JA, Pan Y, et al., The cell of origin dictates the temporal course of neurofibromatosis-1(NF1)low-grade glioma formation[J]. Oncotarget, 2017, 8(29):47206-47215. DOI:10.18632/oncotarget.17589.
[11]Maruoka R, Takenouchi T, Torii C, et al. The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1:A validation study[J]. Genet Test Mol Biomarkers,2014, 18(11):722-735.DOI:10.1089/gtmb.2014.0109.
[12]Koczkowska M, Chen Y, Callens T, et al. Genotype-phenotype correlation in NF1:Evidence for a more severe phenotype associated with missense mutations a ecting NF1 Codons 844–848[J]. Am J Hum Genet, 2018, 102(1):69-87. DOI:10.1016/j.ajhg.2017.12.001.
[13]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.
[14]Imbard A, Pasmant E, Sabbagh A, NF1 single and multi-exons copy number variations in neuro bromatosis type 1[J]. J Hum Genet, 2015,60(4):221-224. DOI:10.1038/jhg.2015.6
[15]Rabara D, Tran TH, Dharmaiah S, et al. KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis[J]. Proc Natl Acad Sci USA,2019, 116(44):22122-22131. DOI:10.1073/pnas.1908353116.
[16]Buske A, Gewies A, Lehmann R, et al. Recurrent NFl gene mutation in a patient with oligosymptomatic neurofibromatosis type1(NF1)[J]. Am J Med Genet, 1999, 86(4):328-330. DOI:10.1002/(sici)1096-8628(19991008)86:4<328::aid-ajmg6>3.0.co;2-o.
[17]Kehrer-Sawatzki H, Mautner VF, Cooper DN. Emerging geno-typephenotype relationships in patients with large NF1 deletions[J]. Hum Genet, 2017, 1369(4):349-376. DOI:10.1007/s00439-017-1766-y.
[18]Pacot L, Vidaud D, Sabbagh A. et al. Severe phenotype in patients with large deletions of NF1[J]. Cancers, 2021, 13(12):2963. DOI:10.3390/cancers13122963.
[19]Messiaen LM, Callens T, Mortier G, et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95%of mutations and reveals a high frequency of unusual splicing defects[J]. Hum Mutat, 2000,15(6):541-555. DOI:10.1002/1098-1004(200006)15:6<541::AIDHUMU6>3.0.CO;2-N.
[20]Mautner VF, Kluwe L, Friedrich RE, et al. Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained1.4 Mb type-1 NF1 deletions[J]. J Med Genet, 2010, 47(9):623-630.DOI:10.1136/jmg.2009.075937.
[21]梅道启,梅世月,陈国洪,等. NF1基因突变致Ⅰ型神经纤维瘤病临床表型及遗传学分析[J].中华神经科杂志, 2020, 53(11):910-917.DOI:10.3760/cma.j.cn113694-20200723-00566.
[22]Pasmant E, Sabbagh A, Hanna N, et al. SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype[J]. J Med Genet, 2009, 46(7):425-430. DOI:10.1136/jmg.2008.065243.
[23]Pasmant E, Parfait B, Luscan A, et al. Neuro bromatosis type 1molecular diagnosis:what can NGS do for you when you have a large gene with loss of function mutations?[J]. Eur J Hum Genet, 2015,23(5):596-601. DOI:10.1038/ejhg.2014.145.
[24]Rasmusen SA, Colman SD, Ho VT, et al. Constitutional an d mosaic large NF1 gene deletions in neurofibromatosis type1[J]. Med Genet,1998, 35(6):468-471. DOI:10.1136/jmg.35.6.468.
[25]Giugliano T, Santoro C, Torella A, et al. Clinical and genetic ndings in children with neuro bromato-sis type 1, Legius syndrome, and other related neurocutaneous disorders[J]. Genes(basel), 2019, 10(8):580.DOI:10.3390/genes10080580.
[26]Parrozzani R, Clementi M, Frizziero L, In vivo detection of choroidal abnormalities related to NF1:Feasibility and comparison with standard NIH diagnostic criteria in pediatric patients[J]. Invest Ophthalmol Vis Sci, 2015, 56(10):6036-6042. DOI:10.1167/iovs.14-16053.
基本信息:
中图分类号:R725.9;R751
引用信息:
[1]王誉涵,陈见友,刘晓雁,等.以咖啡斑为主要表现的神经纤维瘤病患儿NF1基因检测及分析[J].实用皮肤病学杂志,2026,19(01):12-17.
基金信息:
首都儿科研究所临床培育项目（LCYJ-2025-25）
2026-02-10
2026-02-10