Charman Tony, Neilson Tracey C S, Mash Veronica, Archer Hayley, Gardiner Mary T, Knudsen Gun P S, McDonnell Aoibhinn, Perry Jacqueline, Whatley Sharon D, Bunyan David J, Ravn Kirstine, Mount Rebecca H, Hastings Richard P, Hulten Maj, Orstavik Karen Helene, Reilly Sheena, Cass Hilary, Clarke Angus, Kerr Alison M, Bailey Mark E S
Institute of Child Health, University College London, London, UK.
Eur J Hum Genet. 2005 Oct;13(10):1121-30. doi: 10.1038/sj.ejhg.5201471.
We aimed to improve the understanding of genotype-phenotype correlations in Rett syndrome (RS) by adopting a novel approach to categorising phenotypic dimensions - separating typicality of presentation, outcome severity and age of onset - and by classifying MECP2 mutations strictly by predicted functional attributes. MECP2 mutation screening results were available on 190 patients with a clinical diagnosis of RS (140 cases with classic RS, 50 with atypical RS). 135 cases had identified mutations. Of the 140 patients, 116 with classic RS (82.9%) had an identified mutation compared with 19 of 50 patients (38%) with an atypical presentation. Cases with early onset of regression and seizures, and those with clinical features that might indicate alternative aetiologies, were less likely to have mutations. Individuals with late truncating mutations had a less typical presentation than cases with missense and early truncating mutations, presumably reflecting greater residual function of MECP2 protein. Individuals with early truncating mutations had a more severe outcome than cases with missense and late truncating mutations. These findings held when restricting the analysis to cases over 15 years of age and classic cases only. Previous findings of variation in severity among the common mutations were confirmed. The approach to phenotypic and genotypic classification adopted here allowed us to identify genotype-phenotype associations in RS that may aid our understanding of pathogenesis and also contribute to clinical knowledge on the impact of different types of mutations.
我们旨在通过采用一种对表型维度进行分类的新方法——区分临床表现的典型性、结局严重程度和发病年龄，并根据预测的功能属性对MECP2突变进行严格分类，来增进对雷特综合征（RS）基因型-表型相关性的理解。190例临床诊断为RS的患者（140例典型RS，50例非典型RS）有MECP2突变筛查结果。135例检测到突变。在140例患者中，116例典型RS患者（82.9%）检测到突变，相比之下，50例非典型表现患者中有19例（38%）检测到突变。出现退行性变和癫痫发作早发的病例，以及具有可能提示其他病因的临床特征的病例，发生突变的可能性较小。与错义突变和早期截短突变的病例相比，晚期截短突变的个体临床表现不那么典型，这可能反映了MECP2蛋白具有更大的残余功能。早期截短突变的个体比错义突变和晚期截短突变的病例结局更严重。将分析仅限于15岁以上的病例和仅典型病例时，这些发现依然成立。先前关于常见突变之间严重程度存在差异的发现得到了证实。这里采用的表型和基因型分类方法使我们能够识别RS中的基因型-表型关联，这可能有助于我们理解发病机制，也有助于积累关于不同类型突变影响的临床知识。
