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.

Patients with the R133C mutation: is their phenotype different from patients with Rett syndrome with other mutations?

“…No phenotype data; mutations 2 paternal, 1 maternal origin Inui et al 30 2 Japan 3 14 years, no gait apraxia 7 8 years, no head growth deceleration; no severely impaired language; no severe psychomotor retardation Milunsky et al 43 information on their representativeness is not available for the cases from either the Japanese or the United Kingdom, we know that the cases from Australia have been sourced from a national population database and are thus representative of patients with the R133C mutation in this country. The fact that such a sound epidemiological framework has underpinned this particular study provides us with the confidence to generalise the findings.…”

Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X‐linked dominant Conradi‐Hunermann‐Happle syndrome and a mutation in EBP

“…Nevertheless, the molecular confirmation of the L18P mutation in the EBP gene in both the proband (nonmosaic) and his mother, as well as the typical biochemical abnormalities and previously described mild phenotype of the mother, demonstrates the phenotypic spectrum of patients with mutations of EBP. This situation is reminiscent of male patients with neonatal encephalopathy and a strikingly different phenotype from their sisters with typical Rett syndrome, both having the same MECP2 mutation [Milunsky et al, 2001b]. Recognition of these atypical phenotypes in affected males [Meloni et al, 2000;Imessaoudene et al, 2001] will facilitate accurate genetic counseling, carrier testing, and prenatal diagnosis for future pregnancies.…”

The eye-tracking of social stimuli in patients with Rett syndrome and autism spectrum disorders: a pilot study

“…The empirical observation of RS patients points to a relative preservation of social domain, as they have a very intense look and somehow respond to social stimuli. The etiology of RS has strongly been associated with mutations in MECP2 gene 2,3,4 , and more recently with alterations in CDKL5 and FOGX1 in some cases 5,6 . Although it has been ABSTRACT Objective: To compare visual fixation at social stimuli in Rett syndrome (RT) and autism spectrum disorders (ASD) patients.…”