Mutation analysis in Rett syndrome.

Center for Human Genetics and the Department of Pediatrics, Boston University School of Medicine, Boston, MA 02118, USA.
Genetic Testing (Impact Factor: 1.17). 02/2001; 5(4):321-5. DOI: 10.1089/109065701753617462
Source: PubMed

ABSTRACT Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene. Mutations have been demonstrated in more than 80% of females with typical features of Rett syndrome. We identified mutations in the MECP2 gene and documented the clinical manifestations in 65 Rett syndrome patients to characterize the genotype-phenotype spectrum. Bidirectional sequencing of the entire MECP2 coding region was performed. We diagnosed 65 patients with MECP2 mutations. Of these, 15 mutations had been reported previously and 13 are novel. Two patients have multiple deletions within the MECP2 gene. Eight common mutations were found in 43 of 65 patients (66.15%). The majority of patients with identified mutations have the classic Rett phenotype, and several had atypical phenotypes. MECP2 analysis identified mutations in almost all cases of typical Rett syndrome, as well as in some with atypical phenotypes. Eleven (20.4%) of the 54 patients with defined mutations and in whom phenotypic data were obtained did not develop acquired microcephaly. Hence, microcephaly at birth or absence of acquired microcephaly does not obviate the need for MECP2 analysis. We have initiated cascade testing starting with PCR analysis for common mutations followed by sequencing, when necessary. Analysis of common mutations before sequencing the entire gene is anticipated to be the most efficacious strategy to identify Rett syndrome gene mutations.

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    ABSTRACT: Rett syndrome (RTT or RS) is a neurodevelopmental disorder and one of the most frequent genetic diseases in girls. Mutations of the MECP2 gene have been found in a variety of different RTT phenotypes. The MECP2 gene (Xq28) has been described in 1992. Up to now, 218 different mutations have been reported in a total group, of more than 2,100 patients. Mutations in the MECP2 gene are responsible for up to 75% of the classical RTT cases. The mutations, are distributed along the whole gene and are comprised of all types of mutations. Several polymorphisms and benign genetic variants have also been described. Apart from spared reported familial cases, almost all cases are sporadic. RTT syndrome has been considered to be a lethal trait in males. Studying the parental origin of the mutations, however, we and others have found a very high prevalence of de novo mutations on the paternal chromosome. In this work we summarize the mutational reports published until now. One of our aims was to check the mutations' descriptions for consistency and particularly to rename them according to the recommended mutation nomenclature. The increasing number of investigations on the functions of the MeCP2 can help to gain more information about the neuropathogenetic mechanisms causing RTT. Hum Mutat 22:107-115, 2003.
    Human Mutation 09/2003; 22(2):107-15. · 5.05 Impact Factor
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    ABSTRACT: Rett syndrome is an X-linked dominant disorder that usually arises following a single de novo mutation in the MECP2 gene. Point mutation testing and gene dosage analysis of a cohort of British Rett syndrome patients in our laboratory revealed four females who each had two different de novo causative mutations, presumed to be in cis because the patients showed no deviation from the classical Rett syndrome phenotype. Two of these cases had a point mutation and a small intraexonic deletion, a third had a whole exon deletion and a separate small intraexonic deletion, and a fourth case had a small intraexonic deletion and a large duplication. These findings highlight the necessity to perform both point mutation analysis and exon dosage analysis in such cases, particularly because of the possibility of undetected parental mosaicism and the implications for prenatal diagnosis in future pregnancies. These cases also suggest that the MECP2 gene may be particularly prone to multiple mutation events.
    Genetic Testing 09/2008; 12(3):373-5. · 1.17 Impact Factor
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    ABSTRACT: Rett syndrome (RS) is a neurodevelopmental disorder caused by mutations in MECP2 gene. Exons 2, 3, and 4, in addition to intronic and 3'UTR adjacent regions, were sequenced in 80 patients with RS. Twenty-nine sequence variations were detected in 49 patients, 34 (69.4%) patients with the classic form of RS, and 15 (30.6%) patients with atypical forms of RS. Thirteen of the 29 detected mutations represent novel sequence variations. Missense mutation T158M was the most commonly observed mutation, detected in nine patients (11.2%). Six hotspot pathogenic mutations (R133C, T158M, R168X, R255X, R270X, and R294X) were responsible for the phenotype in 26/80 patients (32.5%).
    Brain & development 11/2010; 32(10):843-8. · 1.74 Impact Factor