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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.    Conclusion  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.

A synonymous change, p.Gly16Gly in MECP2 Exon 1, causes a cryptic splice event in a Rett syndrome patient