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
| Autor: | Jiri Zeman, Pavel Martásek, Vladimir Gregor, Daniela Zahorakova, Petra Lelkova, Martin Magner |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine congenital hereditary and neonatal diseases and abnormalities Adolescent Genotype Methyl-CpG-Binding Protein 2 DNA Mutational Analysis Rett syndrome Biology medicine.disease_cause Polymorphism Single Nucleotide MECP2 03 medical and health sciences 0302 clinical medicine Neurodevelopmental disorder X Chromosome Inactivation Rett Syndrome Genetics medicine Humans Genetic Predisposition to Disease Mutation frequency Child Alleles Genetic Association Studies Genetics (clinical) Czech Republic Mutation Point mutation Exons Nucleic acid amplification technique medicine.disease Phenotype 030104 developmental biology Child Preschool Female Nucleic Acid Amplification Techniques 030217 neurology & neurosurgery |
| Zdroj: | Journal of Human Genetics. 61:617-625 |
| ISSN: | 1435-232X 1434-5161 |
| DOI: | 10.1038/jhg.2016.19 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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