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Background  Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder, which is usually caused by  de novo  mutations in the  MECP2  gene. More than 70% of the disease causing  MECP2  mutations are eight recurrent C to T transitions, which almost exclusively arise on the paternally derived X chromosome. About 10% of the RTT cases have a C-terminal frameshift deletion in  MECP2 . Only few RTT families with a segregating  MECP2  mutation, which affects female carriers with a phenotype of mental retardation or RTT, have been reported in the literature. In this study we describe two new RTT families with three and four individuals, respectively, and review the literature comparing the type of mutations and phenotypes observed in RTT families with those observed in sporadic cases. Based on these observations we also investigated origin of mutation segregation to further improve genetic counselling.    Methods   MECP2  mutations were identified by direct sequencing. XCI studies were performed using the X-linked androgen receptor ( AR ) locus. The parental origin of  de novo MECP2  frameshift mutations was investigated using intronic SNPs.    Results  In both families a C-terminal frameshift mutation segregates. Clinical features of the mutation carriers vary from classical RTT to mild mental retardation. XCI profiles of the female carriers correlate to their respective geno-/phenotypes. The majority of the  de novo  frameshift mutations occur on the paternally derived X chromosome (7/9 cases), without a paternal age effect.    Conclusions  The present study suggests a correlation between the intrafamilial phenotypic differences observed in RTT families and their respective XCI pattern in blood, in contrast to sporadic RTT cases where a similar correlation has not been demonstrated. Furthermore, we found  de novo MECP2  frameshift mutations frequently to be of paternal origin, although not with the same high paternal occurrence as in sporadic cases with C to T transitions. This suggests further investigations of more families. This study emphasizes the need for thorough genetic counselling of families with a newly diagnosed RTT patient.

Two new Rett syndrome families and review of the literature: expanding the knowledge of MECP2 frameshift mutations