title: A synonymous change, p.Gly16Gly in MECP2 Exon 1, causes a cryptic splice event in a Rett syndrome patient.
abstract: BACKGROUND
  Mutations in MECP2 are the main cause of Rett Syndrome. To date, no pathogenic synonymous MECP2 mutation has yet been identified. Here, we investigated a de novo synonymous variant c.48C>T (p.Gly16Gly) identified in a girl presenting with a typical RTT phenotype.
  
  
  METHODS
  In silico analyses to predict the effects of sequence variation on mRNA splicing were employed, followed by sequencing and quantification of lymphocyte mRNAs from the subject for splice variants MECP2_E1 and MECP2_E2.
  
  
  RESULTS
  Analysis of mRNA confirmed predictions that this synonymous mutation activates a splice-donor site at an early position in exon 1, leading to a deletion (r.[=, 48_63del]), codon frameshift and premature stop codon (p.Glu17Lysfs*16) for MECP2_E1. For MECP2_E2, the same premature splice site is used, but as this is located in the 5'untranslated region, no effect on the amino acid sequence is predicted. Quantitative analysis that specifically measured this cryptic splice variant also revealed a significant decrease in the quantity of the correct MECP2_E1 transcript, which indicates that this is the etiologically significant mutation in this patient.
  
  
  CONCLUSIONS
  These findings suggest that synonymous variants of MECP2 as well as other known disease genes-and de novo variants in particular- should be re-evaluated for potential effects on splicing.
authors.affiliation: Molecular Neuropsychiatry & Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health, Toronto, Canada.
authors.forename: Taimoor I
authors.initials: TI
authors.lastname: Sheikh
authors.forename: Kirti
authors.initials: K
authors.lastname: Mittal
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Willis
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
mesh_terms: D002675:Child, Preschool; D005091:Exons / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015518:Rett Syndrome / Q000209:etiology* / Q000235:genetics*
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012333:RNA, Messenger