Background: Classical Rett syndrome is a severe neurodevelopmental X-linked dominant disorder affecting 1/15,000 girls worldwide. MECP2 has been identified as the predominant gene associated with Rett syndrome. Approximately 65-85% of patients with classical Rett syndrome have identifiable MECP2 mutations. In comparison, up to 57% of patients with atypical Rett have mutations in the MECP2 gene.
Objectives: To investigate the spectrum and frequency of MECP2 mutations in New Zealand Rett syndrome patients and evaluate whether available clinical criteria were sufficient to direct molecular testing for Rett syndrome.
Patients: and Methods MECP2 coding regions were analysed by direct automated DNA sequencing and multiplex ligation dependent probe assay (MLPA) in samples from 74 patients referred for investigation of possible Rett syndrome. Necessary clinical criteria were examined in detail in 18 patients, with 7/18 having identifiable MECP2 mutations.
Results: Fifteen patients (20%) carried MECP2 mutations, four of which were novel (one insertion mutation, one complex rearrangement and two deletions). Eleven previously described disease-causing sequence changes and several known polymorphisms were also detected. Ninety per cent of the observed point mutations were cytosine to thymidine (C to T) transitions at a CpG dinucleotide. Only three patients with MECP2 mutations displayed all major clinical criteria associated with Rett syndrome, four were atypical cases. Of the patients not having an identified MECP2 mutation, 8 out of 11 had clinical criteria consistent with variant Rett syndrome and one of these had a balanced translocation involving chromosomes 2p25 and 6p11-12.
Conclusions: This is the first genetic study of Rett syndrome in New Zealand patients describing the MECP2 mutational spectrum. The relatively low observed frequency of MECP2 mutations reflects a wide spectrum of mental disability disorders. In some cases there were insufficient clinical criteria to justify referral for Rett gene testing.