Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population.

Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population.

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disease that is primarily characterized by multiple café au-lait spots (CALs) and skin neurofibromas, which are attributed to defects in the tumor suppressor NF1. Because of the age-dependent presentation of NF1, it is often difficult to make an early clinical diagnosis. Moreover, identifying genetic alterations in NF1 patients represents a complex challenge. Currently, there are no effective detective methods, and no comprehensive NF1 mutation data are available for mainland China. We screened 109 Chinese patients from 100 families with NF1-like phenotypes (e.g., CALs, neurofibromas, etc.) using Sanger sequencing, multiplex ligation-dependent probe amplification and cDNA sequencing. NF1 mutations were identified in 97 individuals, among which 34 intragenic mutations have not previously been reported. Our exhaustive mutational analysis detected mutations in 89% (89/100) of the NF1-like probands and 93% (70/75) of subjects fulfilling the National Institutes of Health (NIH) criteria. Our findings indicate that individuals who exclusively present with multiple CALs exhibit a high possibility (76%) of having NF1 and show a significantly lower mutation rate (p = 0.042) compared with subjects who fulfill the NIH criteria, providing clinicians with the information that subjects only with multiple CALs harbor a considerable possibility (24%) of being attributed to other comparable diseases.

1型神经纤维瘤病（NF1）是一种常染色体显性遗传病，主要特征为多发性咖啡斑（CALs）和皮肤神经纤维瘤，这是由肿瘤抑制因子NF1的缺陷所致。由于NF1的症状呈现与年龄相关，早期临床诊断往往很困难。此外，识别NF1患者的基因变异是一项复杂的挑战。目前，没有有效的检测方法，中国大陆也没有全面的NF1突变数据。我们使用桑格测序、多重连接依赖式探针扩增和cDNA测序技术，对100个具有NF1样表型（如咖啡斑、神经纤维瘤等）的家庭中的109名中国患者进行了筛查。在97名个体中发现了NF1突变，其中34种基因内突变此前未曾报道过。我们详尽的突变分析在89%（89/100）的NF1样先证者和93%（70/75）符合美国国立卫生研究院（NIH）标准的受试者中检测到了突变。我们的研究结果表明，仅表现为多发性咖啡斑的个体患NF1的可能性较高（76%），并且与符合NIH标准的受试者相比，其突变率显著较低（p = 0.042），这为临床医生提供了信息，即仅患有多发性咖啡斑的受试者有相当大的可能性（24%）是由其他类似疾病引起的。