Mutation analysis in Rett syndrome.
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 (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
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ABSTRACT: Non-mosaic males with a 46,XY karyotype and a MECP2 null mutation display a phenotype of severe neonatal-onset encephalopathy that is distinctly different from Rett syndrome (RTT). To increase awareness of this rare disorder, we are reporting novel findings in a sporadic case, compare them to 16 previously reported cases and establish salient criteria for clinical diagnosis. The proband suffered from general hypotonia and hypoxia caused by hypoventilation and irregular breathing. He developed abnormal movements, seizures and electroencephalogram abnormalities. He failed to thrive and to reach any motor milestones and died at 15 months from central respiratory failure without a diagnosis. In a muscle biopsy, type II fibers were reduced in diameter, indicating central hypoxia. At autopsy, the brain was small with disproportionate reduction of the frontal and temporal lobes. Synaptophysin staining of synaptic vesicles was greatly reduced in cerebellar and spinal cord sections. Analysis of Golgi-stained pyramidal neurons from cortical layers III and V of the frontal and temporal lobes revealed drastically diminished dendritic trees. Post-mortem MECP2 mutation analysis on DNA and RNA from fibroblasts revealed a novel de novo 9-nucleotide deletion including the intron 3/exon 4 splice junction. The two nucleotides flanking the deletion form a new splice site, and the aberrantly spliced transcript lacks seven nucleotides (r.378_384delTCCCCAG), causing a frameshift and premature termination codon (p.I126fsX11). Males with congenital encephalopathy, not females with RTT, represent the true human counterpart for the commonly studied Mecp2-/y mouse model and provide unique insight into the mechanisms of MeCP2 deficiency.Clinical Genetics 06/2008; 74(2):116-26. · 4.25 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