Department of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Greece.
Department of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Greece.
J Neurol Sci. 2018 Dec 15;395:95-105. doi: 10.1016/j.jns.2018.10.006. Epub 2018 Oct 4.
Neurofibromatosis Type 1 (NF1) is caused by mutations of the NF1 gene. The aim of this study was to identify the genetic causes underlying the disease, attempt possible phenotype/genotype correlations and add to the NF1 mutation spectrum. A screening protocol based on genomic DNA was established in 168 patients, encompassing sequencing of all coding exons and adjoining introns using a custom targeted next generation sequencing protocol and subsequent confirmation of findings with Sanger sequencing. MLPA was used to detect deletions/duplications and positive findings were confirmed by RNA analysis. All novel findings were evaluated according to ACMG Standards and guidelines for the interpretation of sequence variants with the aid of in-silico bioinformatic tools and family segregation analysis. A germline variant was identified in 145 patients (86%). In total 49 known and 70 novel variants in coding and non-coding regions were identified. Seven patients carried whole or partial gene deletions. NF1 patients, present with high phenotypic variability even in cases where the same germline disease causing variant has been identified. Our findings will contribute to a better knowledge of the genetic causes and the phenotypic expression related to the disease.
神经纤维瘤病 1 型（NF1）是由 NF1 基因突变引起的。本研究旨在确定该疾病的遗传原因，尝试可能的表型/基因型相关性，并增加 NF1 突变谱。在 168 名患者中建立了基于基因组 DNA 的筛选方案，使用定制的靶向下一代测序方案对所有编码外显子和相邻内含子进行测序，并使用 Sanger 测序对结果进行后续确认。使用 MLPA 检测缺失/重复，并通过 RNA 分析确认阳性发现。所有新发现均根据 ACMG 标准和指南进行评估，根据序列变异的解释，借助于计算机生物信息学工具和家族分离分析。在 145 名患者（86%）中发现了种系变异。总共鉴定出 49 个已知和 70 个编码和非编码区域的新变异。7 名患者携带整个或部分基因缺失。NF1 患者的表型存在高度变异性，即使在确定了相同的种系致病变异的情况下也是如此。我们的发现将有助于更好地了解与疾病相关的遗传原因和表型表达。
