Abstract：
BACKGROUND: Neurofibromatosis type 1 (NF1) is a highly heterogeneous autosomal genetic disorder characterized by a broad spectrum of clinical and molecular manifestations. The correlations between genotype and phenotype in NF1 remain elusive. This study aimed to elucidate genotype-phenotype associations in a large Chinese cohort of NF1 patients.
METHODS: We included NF1 patients from our center who underwent genetic testing for NF1 variants and systemic examination. Genotype-phenotype correlation analyses were performed, focusing on variation types and involved neurofibromin domains.
RESULTS: A total of 195 patients were enrolled, comprising 105 males and 90 females, with a median age of 18 years. Truncating variants, single amino acid variations, and splicing variants accounted for 139/195 (71.3%), 23/195 (11.8%), and 33/195 (16.9%), respectively. Patients with splicing variants exhibited a significantly higher prevalence of spinal plexiform neurofibromas (spinal PNF) than those with truncating variants (76.4% vs. 51.8%; p = 0.022). Variations affecting the PKC domain were associated with higher rates of cutaneous neurofibromas (CNF) (100% vs. 64.9%, p < 0.001), Lisch nodules (100% vs. 61.2%, p < 0.001), plexiform neurofibromas (PNF) (100% vs. 95.7%, p = 0.009), and psychiatric disorders (11.8% vs. 1.6%, p = 0.042). Patients with mutations in the CSRD had an elevated risk of secondary primary malignancies (11.6% vs. 2.8%, p = 0.015). GRD involvement might enhance the risk of Lisch nodules (76.9% vs. 53.7%, p = 0.044). Variations in the Sec14-PH domain were correlated with a higher rate of CNF (76.8% vs. 58.6%, p = 0.014). Additionally, we found that the p.R1748* variants carry a high risk of malignancy.
CONCLUSIONS: Our study suggested some novel genotype-phenotype correlations within a Chinese cohort, providing innovative insights into this complex field that may contribute to genetic counseling, risk stratification, and clinical management for the NF1 population.
METHODS: We included NF1 patients from our center who underwent genetic testing for NF1 variants and systemic examination. Genotype-phenotype correlation analyses were performed, focusing on variation types and involved neurofibromin domains.
RESULTS: A total of 195 patients were enrolled, comprising 105 males and 90 females, with a median age of 18 years. Truncating variants, single amino acid variations, and splicing variants accounted for 139/195 (71.3%), 23/195 (11.8%), and 33/195 (16.9%), respectively. Patients with splicing variants exhibited a significantly higher prevalence of spinal plexiform neurofibromas (spinal PNF) than those with truncating variants (76.4% vs. 51.8%; p = 0.022). Variations affecting the PKC domain were associated with higher rates of cutaneous neurofibromas (CNF) (100% vs. 64.9%, p < 0.001), Lisch nodules (100% vs. 61.2%, p < 0.001), plexiform neurofibromas (PNF) (100% vs. 95.7%, p = 0.009), and psychiatric disorders (11.8% vs. 1.6%, p = 0.042). Patients with mutations in the CSRD had an elevated risk of secondary primary malignancies (11.6% vs. 2.8%, p = 0.015). GRD involvement might enhance the risk of Lisch nodules (76.9% vs. 53.7%, p = 0.044). Variations in the Sec14-PH domain were correlated with a higher rate of CNF (76.8% vs. 58.6%, p = 0.014). Additionally, we found that the p.R1748* variants carry a high risk of malignancy.
CONCLUSIONS: Our study suggested some novel genotype-phenotype correlations within a Chinese cohort, providing innovative insights into this complex field that may contribute to genetic counseling, risk stratification, and clinical management for the NF1 population.
摘要：
背景：1型神经纤维瘤病（NF1）是一种高度异质性的常染色体遗传病，其特征是具有广泛的临床和分子表现。NF1中基因型和表型之间的相关性仍然难以捉摸。本研究旨在阐明大量中国NF1患者队列中的基因型-表型关联。
方法：我们纳入了我们中心的NF1患者，他们接受了NF1变异基因检测和系统检查。进行基因型-表型相关性分析，侧重于变异类型和涉及的神经纤维蛋白结构域。
结果：共纳入195名患者，包括105名男性和90名女性，平均年龄为18岁。截断变体，单氨基酸变异，剪接变体占139/195（71.3%），23/195（11.8%），和33/195（16.9%），分别。剪接变体患者的脊髓丛状神经纤维瘤（spinalPNF）患病率明显高于截短变体患者（76.4％vs.51.8%；p=0.022）。影响PKC结构域的变异与较高的皮肤神经纤维瘤（CNF）发病率相关（100％vs.64.9%,p<0.001)，Lisch结节（100％vs.61.2%,p<0.001)，丛状神经纤维瘤（PNF）（100％vs.95.7%,p=0.009),和精神疾病(11.8%vs.1.6%,p=0.042)。CSRD突变患者继发原发性恶性肿瘤的风险升高（11.6％vs.2.8%，p=0.015)。GRD参与可能会增加Lisch结节的风险(76.9%vs.53.7%,p=0.044)。Sec14-PH域的变异与更高的CNF率相关(76.8%vs.58.6%,p=0.014)。此外,我们发现p.R1748*变异体具有很高的恶性肿瘤风险.
结论：我们的研究表明，在一个中国队列中，一些新的基因型-表型相关性，为这个复杂的领域提供创新的见解，可能有助于遗传咨询，风险分层，和NF1人群的临床管理。
方法：我们纳入了我们中心的NF1患者，他们接受了NF1变异基因检测和系统检查。进行基因型-表型相关性分析，侧重于变异类型和涉及的神经纤维蛋白结构域。
结果：共纳入195名患者，包括105名男性和90名女性，平均年龄为18岁。截断变体，单氨基酸变异，剪接变体占139/195（71.3%），23/195（11.8%），和33/195（16.9%），分别。剪接变体患者的脊髓丛状神经纤维瘤（spinalPNF）患病率明显高于截短变体患者（76.4％vs.51.8%；p=0.022）。影响PKC结构域的变异与较高的皮肤神经纤维瘤（CNF）发病率相关（100％vs.64.9%,p<0.001)，Lisch结节（100％vs.61.2%,p<0.001)，丛状神经纤维瘤（PNF）（100％vs.95.7%,p=0.009),和精神疾病(11.8%vs.1.6%,p=0.042)。CSRD突变患者继发原发性恶性肿瘤的风险升高（11.6％vs.2.8%，p=0.015)。GRD参与可能会增加Lisch结节的风险(76.9%vs.53.7%,p=0.044)。Sec14-PH域的变异与更高的CNF率相关(76.8%vs.58.6%,p=0.014)。此外,我们发现p.R1748*变异体具有很高的恶性肿瘤风险.
结论：我们的研究表明，在一个中国队列中，一些新的基因型-表型相关性，为这个复杂的领域提供创新的见解，可能有助于遗传咨询，风险分层，和NF1人群的临床管理。
