Spectrum of MECP2 mutations in New Zealand Rett syndrome patients.
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.


OBJECTIVE
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.


METHODS
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.
Raizis
Anthony M
AM
Department of Molecular Pathology, Canterbury Health Laboratories, PO Box 151, Christchurch, New Zealand.
Saleem
Mohammed
M
MacKay
Richard
R
George
Peter M
PM
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009520:New Zealand; D010641:Phenotype; D011597:Psychomotor Performance; D015518:Rett Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000523:psychology; D055815:Young Adult
C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2