MeCP2 mutations in children with and without the phenotype of Rett syndrome

Background: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. Method s: One hundred sixteen patients with classical and atypical RTT were studie d for mutations of the MeCP2 gene by using DHPLC and direct sequencing. Res ults: Causative mutations in the MeCP2 gene were identified in 63% of patie nts, representing a total of 30 different mutations. Mutations were identif ied in 72% of patients with classical RTT and one third of atypical cases s tudied (8 of 25). The authors found 17 novel mutations, including a complex gene rearrangement found in one individual involving two deletions and a d uplication. The duplication was identical to a region within the 3 ' untran slated region (UTR), and represents the first report of involvement of the 3 ' UTR in RTT. The authors also report the identification of MeCP2 mutatio ns in two males; a Klinefelter's male with classic RTT (T158M) and a hemizy gous male infant with a Xq27-28 inversion and a novel 32 bp frameshift dele tion [1154(delS2)]. Studies examining the relationship between mutation typ e, X-inactivation status, and severity of clinical presentation found signi ficant differences in clinical presentation between different types of muta tions. Mutations in the amino-terminus were significantly correlated with a more severe clinical presentation compared with mutations closer to the ca rboxyl-terminus of MeCP2. Skewed X-inactivation patterns were found in two asymptomatic carriers of MeCP2 mutations and six girls diagnosed with eithe r atypical or classical RTT. Conclusion: This patient series confirms the h igh frequency of MeCP2 gene mutations causative of RTT in females and provi des data concerning the molecular basis for clinical variability (mutation type and position and X-inactivation patterns).