Rett综合征患儿MECP2基因型和表型关系研究

Correlation between MECP2 genotype and phenotype in Chinese patients with Rett syndrome

目的寻找中国Rett综合征（RTT）患儿甲基化CpG结合蛋白2基因（MECP2）突变的基因型和表型之间的相互关系，为临床诊断和治疗提供帮助。方法对126例经分子遗传学方法诊断的RTT患儿的临床表型参照Kerr等和Scala等评分标准进行打分，采用SPSS12．0软件包进行统计分析。结果分析MECP2突变类型、基因功能区和表型的关系显示，位于基因不同功能区的突变：甲基化CpG结合区（MBD）、转录抑制区（TRD）和C末端（CTS）对RTT表型的影响差异无统计学意义（P〉0．05）；不同突变类型：错义、无义、移码和大片段缺失突变对RTT表型的影响差异无统计学意义（P〉0．05）。分析MECP2突变类型和基因功能区共同对表型的影响显示：同位于MBD的无义和错义突变相比较，前者临床严重性评分高于后者，差异有统计学意义（P=0．016），而位于TRD的无义和错义突变临床严重性评分之间差异无统计学意义（P〉0．05）；位于MBD和TRD的错义突变的临床严重性评分之间差异无统计学意义（P〉0．05），位于MBD和TRD的无义突变的临床严重性评分之间差异无统计学意义（P〉0．05）。分析MECP2最常见突变类型和表型的关系显示：P．T158M、P．R168X、c．806delG和P．R255X对RTT表型总的影响差异无统计学意义（P〉0．05），但在语言功能的受累程度上，以上4种突变之间差异有统计学意义（P=0．028），且语言能力受损的发生率差异也有统计学意义（P=0．019）。结论MECP2基因型和表型之间存在一些相互关系：位于MBD的无义突变病情较严重；在〈5岁组中发生频率较高的4种突变对语言功能和语言能力受损发生率方面存在不同，其中P．R168X受损最重。

Objective Rett syndrome （RTT） is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. The aim of this study was to investigate the correlation between MECP2 genotype and phenotype and thereby not only to provide assistance for clinical care, but also facilitate clinical genetic counseling. Method Individual phenotype characteristic and clinical severity of 126 children with RTT diagnosed by molecular genetic methods were evaluated by using scales of Kerr et al and Scala et al. Statistical package SPSS 12. 0 was used for analyses of data. Since the majority of the data were not normally distributed, non-parametric tests were used. The Kruskal-Wallis test/ Wilcoxon Mann-Whitney test was employed to compare total severity phenotype scores. The Fisher exact test was used for comparing rates. Statistical significance was set at P 〈 0. 05. Result There were no significant differences in the average overall scores for RTT patients with mutations in the region of methyl-CpG-binding domain （MBD） compared with those mutations in the transcription repression domain （TRD） and C terminal segment （CTS）, also patients with nonsense mutations compared with missense mutations, frameshift mutations and large deletions （P 〉 0. 05）. The RTT patients with nonsense mutations located in the region of MBD have more severe phenotype than those with missense mutations in the same region （ P = 0. 016）. Among p. T158M, p. R168X, c. 806delG and p. R255X, there were no significant differences in the average overall scores （ P 〉 0. 05 ）, but there were significant differences in language skill （ P = 0. 028 ） and in language impairment rate at different level （P = 0. 019）. Conclusion There are relationships between MECP2 genotype and phenotype：the RTT patients with nonsense mutations located in MBD tend to develop more severe phenotype;there are significant differences in language skill and language impairment rate in the groups with p. T158M, p. R168X, c. 806del and p. R255X, which had higher frequency in children below five-years of age and the p. R168X present with most severe impairment.