Investigating genotype-phenotype relationships in Rett syndrome using an international data set
Investigating genotype-phenotype relationships in Rett syndrome using an international data set
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DOI：
10.1212/01.wnl.0000304752.50773.ec
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发表时间：
2008-03-11
期刊：
影响因子：
9.9
通讯作者：
Leonard, H.
中科院分区：
文献类型：
--
作者：
Bebbington, A.;Anderson, A.;Leonard, H.
背景：Rett综合征是一种罕见的神经发育障碍，发病率为1：9000。主要的遗传原因在1999年首次报道，当时发现与甲基CpG结合蛋白2(或MECP2)基因突变有关。这项研究使用大型国际数据库InterRett的数据来检查基因表型关系，并将这些数据与基于人群的队列中先前的发现进行比较。方法：这些分析的数据集来自InterRett病例的子集，其主题信息收集自家庭、临床医生或两者。用3个量表比较已知的8个已知的复发致病MECP2突变和272例C末端缺失患者的个体表型特征和临床严重程度。结果：总的来说，p.R270X和p.R255X是最严重的突变，p.R133C和p.R294X是最轻微的突变。不同突变的个体表型特征有显著差异，如手的使用、行走和语言。结论：对Rett综合征MECP2突变表型相关性的多中心研究提供了比迄今为止对与常见突变相关的特定表型特征更深入的了解。尽管X失活对临床严重程度的修饰影响不能包括在分析中，但这一发现证实了Rett综合征明显的基因-表型关系，并表明合作的好处对罕见疾病的有效研究至关重要。
Background: 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.Method: 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).Results: 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.Conclusions: 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.