van Minkelen R, van Bever Y, Kromosoeto J N R, Withagen-Hermans C J, Nieuwlaat A, Halley D J J, van den Ouweland A M W
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Clin Genet. 2014 Apr;85(4):318-27. doi: 10.1111/cge.12187. Epub 2013 Jun 25.
NF1 mutations are the underlying cause of neurofibromatosis type 1 (NF1), a neuro-cardio-facio-cutaneous syndrome (NCFC). Because of the clinical overlap between NCFCs, genetic analysis of NF1 is necessary to confirm a clinical diagnosis NF1. This report describes the clinical and genetic findings of 18 years of NF1 molecular diagnostics in the Netherlands. A pathogenic mutation was found in 59.3% (1178/1985) of the index patients, mostly de novo (73.8%). The majority of the index patients (64.3%) fulfilled the National Institute of Health NF1 criteria, a pathogenic mutation was found in 80.9% of these patients. Seventy-four percent of the index patients with an NF1 pathogenic mutation and not fulfilling the NF1 criteria is <12 years, in agreement with the fact that some NF1 symptoms appear after puberty. Genotype-phenotype correlations were studied for 527 index patients. NF1 patients with a type 1 microdeletion have a sixfold higher risk of special education vs NF1 patients with an intragenic mutation. No evidently milder NF1 phenotype for patients with a missense mutation was observed. Forty-six prenatal analyses were performed in 28 (2.4%) families, of which 29 (63%) showed heterozygosity for the familial pathogenic mutation. This indicates that there is a need for prenatal NF1 testing.
NF1突变是1型神经纤维瘤病（NF1）的根本病因，1型神经纤维瘤病是一种神经 - 心脏 - 面部 - 皮肤综合征（NCFC）。由于NCFCs之间存在临床重叠，因此对NF1进行基因分析对于确诊NF1临床诊断是必要的。本报告描述了荷兰18年NF1分子诊断的临床和基因研究结果。在59.3%（1178/1985）的索引患者中发现了致病突变，其中大多数为新发突变（73.8%）。大多数索引患者（64.3%）符合美国国立卫生研究院的NF1标准，在这些患者中80.9%发现了致病突变。74%携带NF1致病突变但不符合NF1标准的索引患者年龄小于12岁，这与一些NF1症状在青春期后出现的事实相符。对527名索引患者进行了基因型 - 表型相关性研究。与携带基因内突变的NF1患者相比，携带1型微缺失的NF1患者接受特殊教育的风险高六倍。未观察到错义突变患者的NF1表型明显较轻。在28个（2.4%）家庭中进行了46次产前分析，其中29次（63%）显示对家族性致病突变呈杂合性。这表明需要进行NF1产前检测。
