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

Kirstine Ravn,Gitte Roende,Jytte B Nielsen,Kathrine Fuglsang,Kristin L Eiklid,Zeynep Tümer,Ola H Skjeldal,Morten Duno

doi:10.1186/1750-1172-6-58

Abstract

BackgroundRett 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.MethodsMECP2 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.ResultsIn 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.ConclusionsThe 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.

Highlights

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder, which is usually caused by de novo mutations in the methyl-CpG-binding protein 2 (MECP2) gene
We compare the type of mutations observed in RTT families to those of sporadic cases and we present our study on the parental origin of de novo MECP2 frameshift mutations in our RTT cohort
Clinical evaluation The patients have been clinically evaluated according to the consensus RTT criteria described in 2001 [1], in order to compare their clinical profiles with previously published family members with RTT and further to the current revised diagnostic criteria from 2010 [21]

Summary

Introduction

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. 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 investigated origin of mutation segregation to further improve genetic counselling. Hemizygous males with de novo or familial MECP2 mutations often have frameshift mutations caused either by single-nucleotide deletions/ insertions or by small intragenic rearrangements [8,9]

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Discussion

Conclusion