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: 1.65). 02/2001; 5(4):321-5. DOI: 10.1089/109065701753617462
Source: PubMed


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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    • "Various studies point to a possible genotype–phenotype correlation in some recurrent variations detected in this study. Missense mutations D97Y and A378G are associated with classical RS [25] [26] [27] [28]. Mutations R133C, P152R, and T158M are associated either classical [7] [29] and atypical forms of RS [30] [31] [32]. "
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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. DOI:10.1016/j.braindev.2009.11.007 · 1.88 Impact Factor
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    ABSTRACT: X-linked dominant Conradi-Hunermann-Happle syndrome (CDPX2; MIM 302960) is a rare chondrodysplasia punctata primarily affecting females. CDPX2 is presumed lethal in males, although a few affected males have been reported. CDPX2 is a cholesterol biosynthetic disorder due to 3-beta-hydroxysteroid-delta8,delta7-isomerase deficiency caused by mutations in the emopamil binding protein (EBP) gene. A 2.5-year-old Caucasian male was followed from the age of 6 weeks and noted to have significant developmental delay, hypotonia, seizures, and patchy hypopigmentation. Multiple congenital anomalies included a unilateral cataract, esotropia, crossed renal ectopia, stenotic ear canals, and failure to thrive, requiring G-tube placement. Multiple minor anomalies and ptosis were noted. No skeletal asymmetry or chondrodysplasia punctata were noted on skeletal survey at 6 weeks and 13 months. An extensive genetic work-up including cholesterol (126-176 mg/dl) and 7-dehydrocholesterol was unrevealing. However, the levels of 8(9)-cholestenol and 8-dehydrocholesterol were mildly increased in plasma, which was confirmed in cultured fibroblasts. This prompted molecular analysis of the EBP gene, which revealed a novel hemizygous (nonmosaic) mutation in exon 2 (L18P). Two restriction digests were developed that confirmed this mutation in skin fibroblasts, blood, and buccal cells (all nonmosaic). We determined that the patient's mother (adopted) also has the L18P mutation enabling prenatal diagnosis of a normal male fetus. She has normal stature, no asymmetry, no cataracts at this time, and has a patch of hyperpigmentation on her chest best visualized on Woods lamp examination, characteristic of CDPX2. The mild maternal phenotype has been described previously. However, this nonmosaic missense mutation has resulted in a severe phenotype in her surviving son.
    American Journal of Medical Genetics Part A 01/2003; 116A(3):249-54. DOI:10.1002/ajmg.a.10849 · 2.16 Impact Factor
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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 08/2003; 22(2):107-15. DOI:10.1002/humu.10243 · 5.14 Impact Factor
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