Bebbington A, Anderson A, Ravine D, Fyfe S, Pineda M, de Klerk N, Ben-Zeev B, Yatawara N, Percy A, Kaufmann W E, Leonard H
Telethon Institute of Child Health Research, PO Box 855, West Perth, Western Australia 6872, Australia.
Neurology. 2008 Mar 11;70(11):868-75. doi: 10.1212/01.wnl.0000304752.50773.ec.
Rett syndrome is an uncommon neurodevelopmental disorder with an incidence of 1:9,000 live female births. The principal genetic cause was first reported in 1999 when the association with mutations in the methyl-CpG-binding protein 2 (or MECP2) gene was identified. This study uses data from a large international database, InterRett, to examine genotype-phenotype relationships and compares these with previous findings in a population-based cohort.
The data set for these analyses was derived from a subset of InterRett cases with subject information collected from the family, the clinician, or both. Individual phenotypic characteristics and clinical severity using three scales were compared among those with eight known recurrent pathogenic MECP2 mutations as well as those with C-terminal deletions (n = 272).
Overall, p.R270X and p.R255X were the most severe and p.R133C and p.R294X were the mildest mutations. Significant differences by mutation were seen for individual phenotypic characteristics such as hand use, ambulation, and language.
This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations. Although the modifying influence of X inactivation on clinical severity could not be included in the analysis, the findings confirm clear genotype-phenotype relationships in Rett syndrome and show the benefits of collaboration crucial to effective research in rare disorders.
雷特综合征是一种罕见的神经发育障碍，活产女婴发病率为1:9000。1999年首次报道了其主要遗传病因，当时发现与甲基化CpG结合蛋白2（或MECP2）基因突变有关。本研究使用来自大型国际数据库InterRett的数据，以研究基因型与表型的关系，并将其与之前基于人群队列的研究结果进行比较。
这些分析的数据集来自InterRett病例的一个子集，其受试者信息是从家庭、临床医生或两者处收集的。在有8种已知复发性致病性MECP2突变的患者以及有C末端缺失的患者（n = 272）中，比较了使用三种量表的个体表型特征和临床严重程度。
总体而言，p.R270X和p.R255X是最严重的突变，p.R133C和p.R294X是最轻微的突变。在诸如手部使用、行走和语言等个体表型特征方面，不同突变存在显著差异。
这项对雷特综合征中MECP2突变表型相关性的多中心研究，比以往对常见突变相关的具体表型特征的了解有了更深入的认识。尽管X染色体失活对临床严重程度的修饰影响未纳入分析，但研究结果证实了雷特综合征中明确的基因型-表型关系，并显示了合作对于罕见病有效研究的关键作用。
