A study of the genetic epidemiology of Rett syndrome and the causes of phenotypic variability

Rett syndrome (FlTT) is a severe neurological disorder that primarily affects females, with an incidence of approximately 1:10 000. RTT shows marked clinical variability in its presentation. Mutations in the X-linked Methyl-CpG-Binding Protein 2 (MECPZ) have been found in approximately 65% of cases. The MeCP2 protein binds methylated DNA via a Methyl Binding Domain (MBD), and recruits a silencing complex via a Transcription Repression Domain (TRD). The aim of the present study was to investigate the causes for phenotypic variability in R'lT, in the hope of understanding its aetiology and prognosis. A large, clinically well characterised cohort of RTT patients was utilised to investigate the incidence of MECP2 mutations and phenotypic correlations with different mutations and skewing of X-inactivation. Truncation mutations were associated with a more severe phenotype in general, as were early mutations affecting the Methyl-Binding Domain (MBD). The incidence of skewing of X-inactivation was significantly increased in RTT patients compared to normal female populations. Varying degrees of skewing in individual mutant cell lines were associated with differences in protein function. Different mutations also altered protein function in different ways in these cell lines. A proportion of RTT cases may have mutations in genes other than MECP2. A family has been described with no pathogenic MECP2 mutation. The ARX gene was screened in this family, but no mutations were found. Future work will examine other genes that may be responsible for RTT in a minority of cases. In conclusion, the phenotypic variability observed in RTT appears to arise from several interacting factors. Protein function and phenotypic outcome may vary depending on the mutation and the importance of particular residues for protein structure or function. Varying degrees of skewing of X-inactivation may then modify these effects. In addition, a small proportion of RTT cases may be phenocopies resulting from mutations in other genes