Human Molecular Genetics Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, No.5, Fushing Street, Kweishan, Taoyuan, Taiwan.
Division of Genetics and Endocrinology, Department of Pediatrics, Chang Gung University College of Medicine and Chang Gung Children's and Memorial Hospital, No.5, Fushing Street, Kweishan, Taoyuan, Taiwan.
J Biomed Sci. 2018 Oct 5;25(1):72. doi: 10.1186/s12929-018-0474-9.
Neurofibromatosis type 1 (NF1) is a dominantly inherited tumor predisposition syndrome that targets the peripheral nervous system. It is caused by mutations of the NF1 gene which serve as a negative regulator of the cellular Ras/MAPK (mitogen-activated protein kinases) signaling pathway. Owing to the complexity in some parts of clinical diagnoses and the need for better understanding of its molecular relationships, a genetic characterization of this disorder will be helpful in the clinical setting.
In this study, we present a customized targeted gene panel of NF1/KRAS/BRAF/p53 and SPRED1 genes combined with Multiple Ligation-Dependent Probe Amplification analysis for the NF1 mutation screening in a cohort of patients clinically suspected as NF1.
In this study, we identified 73 NF1 mutations and two BRAF novel variants from 100 NF1 patients who were suspected as having NF1. These genetic alterations are heterogeneous and distribute in a complicated way without clustering in either cysteine-serine-rich domain or within the GAP-related domain. We also detected fifteen multi-exon deletions within the NF1 gene by MLPA Analysis.
Our results suggested that a genetic screening using a NGS panel with high coverage of Ras-signaling components combined with Multiple Ligation-Dependent Probe Amplification analysis will enable differential diagnosis of patients with overlapping clinical features.
神经纤维瘤病 1 型（NF1）是一种显性遗传的肿瘤易感性综合征，靶向外周神经系统。它是由 NF1 基因突变引起的，NF1 基因作为细胞 Ras/MAPK（丝裂原激活蛋白激酶）信号通路的负调节剂。由于临床诊断的某些部分较为复杂，并且需要更好地了解其分子关系，因此对该疾病进行基因特征分析将有助于临床诊断。
在这项研究中，我们提出了一种定制的靶向 NF1/KRAS/BRAF/p53 和 SPRED1 基因的基因panel，并结合多重连接依赖性探针扩增分析，对临床疑似 NF1 的患者队列进行 NF1 基因突变筛查。
在这项研究中，我们从 100 名疑似患有 NF1 的 NF1 患者中鉴定出了 73 种 NF1 突变和两种 BRAF 新变体。这些遗传改变是异质性的，分布方式复杂，既不在半胱氨酸-丝氨酸丰富域内，也不在 GAP 相关域内聚集。我们还通过 MLPA 分析检测到 NF1 基因内的十五个多外显子缺失。
我们的研究结果表明，使用包含高覆盖 Ras 信号成分的 NGS panel 结合多重连接依赖性探针扩增分析进行基因筛查，将有助于对具有重叠临床特征的患者进行鉴别诊断。
