title: MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning.
abstract: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by developmental regression with loss of motor, communication and social skills, onset of stereotypic hand movements and often seizures. RTT is primarily caused by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). We established a high-resolution melting (HRM) technique for mutation scanning of the MECP2 gene and performed analyses in Czech patients with RTT, autism spectrum conditions and intellectual disability with Rett-like features. In the cases with confirmed MECP2 mutations, we determined X-chromosome inactivation (XCI), examined the relationships between genotype and clinical severity and evaluated the modifying influence of XCI. Our results demonstrate that HRM analysis is a reliable method for the detection of point mutations, small deletions and duplications in the MECP2 gene. We identified 29 pathogenic mutations in 75 girls, including four novel mutations: c.155_1189del1035;909_932inv;insC, c.573delC, c.857_858dupAA and c.1163_1200del38. Skewed XCI (ratio >75%) was found in 19.3% of the girls, but no gross divergence in clinical severity was observed. Our findings confirm a high mutation frequency in classic RTT (92%) and a correlation between the MECP2 mutation type and clinical severity. We also demonstrate limitations of XCI in explaining all of the phenotypic differences in RTT.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: Daniela
authors.initials: D
authors.lastname: Zahorakova
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Lelkova
authors.affiliation: Department of Medical Genetics, Thomayer Hospital, Prague, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gregor
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Magner
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Zeman
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Martasek
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D018153:Czech Republic; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D009154:Mutation; D021141:Nucleic Acid Amplification Techniques; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015518:Rett Syndrome / Q000175:diagnosis* / Q000235:genetics*; D049951:X Chromosome Inactivation
chemical_list: D051783:Methyl-CpG-Binding Protein 2