Evans D G, Bowers N, Burkitt-Wright E, Miles E, Garg S, Scott-Kitching V, Penman-Splitt M, Dobbie A, Howard E, Ealing J, Vassalo G, Wallace A J, Newman W, Huson S M
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Institute of Human Development, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK.
Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK.
EBioMedicine. 2016 May;7:212-20. doi: 10.1016/j.ebiom.2016.04.005. Epub 2016 Apr 13.
The detection rate for identifying the underlying mutation in neurocutaneous syndromes is affected by the sensitivity of the mutation test and the heterogeneity of the disease based on the diagnostic criteria. Neurofibromatosis type (NF1) has been defined for 29years by the National Institutes for Health (NIH) criteria which include ≥6 Café au Lait macules (CAL) as a defining criterion. The discovery of SPRED1 as a cause of Legius syndrome which is manifested by CAL, freckling and learning difficulties has introduced substantial heterogeneity to the NIH criteria.
We have defined the sensitivity of comprehensive RNA analysis on blood of presumed NF1 patients meeting NIH criteria with at least one nonpigmentary criterion and determined the proportion of children with ≥6 CAL and no family history that has an NF1 or SPRED1 genetic variant. RNA analysis was carried out from 04/2009-12/2015 on 361 NF1 patients.
A presumed causative NF1 mutation was found in 166/171 (97.08%-95% CI 94.56-99.6%) of familial cases and 182/190 (95.8%-95% CI 92.93-98.65%) sporadic de novo cases. Two of thirteen (15%) mutation negative individuals had dysembryoplastic neuroepithelial tumour (DNET) compared to 2/348 (0.6%) with an NF1 variant (p=0.007). No SPRED1 variants were found in the thirteen individuals with no NF1 variant. Of seventy-one individuals with ≥6 CAL and no non-pigmentary criterion aged 0-20years, 47 (66.2%) had an NF1 variant six (8.5%) a SPRED1 variant and 18 (25.3%) no disease causing variant. Using the 95.8% detection rate the likelihood of a child with ≥6 CAL having constitutional NF1 drops from 2/3 to 1/9 after negative RNA analysis.
RNA analysis in individuals with presumed NF1 has high sensitivity and includes a small subset with DNET without an NF1 variant. Furthermore negative analysis for NF1/SPRED1 provides strong reassurance to children with ≥6 CAL that they are unlikely to have NF1.
基于诊断标准，神经皮肤综合征潜在突变的检出率受突变检测灵敏度和疾病异质性的影响。神经纤维瘤病1型（NF1）依据美国国立卫生研究院（NIH）标准已定义了29年，该标准将≥6块咖啡牛奶斑（CAL）作为一项定义标准。SPRED1被发现是Legius综合征的病因，该综合征表现为CAL、雀斑和学习困难，这给NIH标准带来了显著的异质性。
我们确定了对符合NIH标准且至少有一项非色素沉着标准的疑似NF1患者血液进行全面RNA分析的灵敏度，并确定了≥6块CAL且无家族病史的儿童中携带NF1或SPRED1基因变异的比例。2009年4月至2015年12月对361例NF1患者进行了RNA分析。
在166/171例（97.08%，95%可信区间94.56 - 99.6%）家族性病例和182/190例（95.8%，95%可信区间92.93 - 98.65%）散发性新生病例中发现了疑似致病的NF1突变。13例突变阴性个体中有2例（15%）患有胚胎发育不良性神经上皮肿瘤（DNET），相比之下，348例携带NF1变异的个体中有2例（0.6%）（p = 0.007）。在13例无NF1变异的个体中未发现SPRED1变异。在71例年龄0 - 20岁、有≥6块CAL且无非色素沉着标准的个体中，47例（66.2%）有NF1变异，6例（8.5%）有SPRED1变异，18例（25.3%）无致病变异。使用95.8%的检出率，RNA分析阴性后，有≥6块CAL的儿童患先天性NF1的可能性从2/3降至1/9。
对疑似NF1个体进行RNA分析具有高灵敏度，且包括一小部分患有DNET但无NF1变异的患者。此外，NF1/SPRED1的阴性分析为有≥6块CAL的儿童提供了有力的保证，即他们不太可能患有NF1。
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