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MECP2 analysis in mentally retarded patients: implications for routine DNA diagnostics
Tjitske Kleefstra1, Helger G Yntema, Willy M Nillesen
1Department of Human Genetics, University Medical Centre St Radboud, PO Box 9101, Nijmegen 6500 HB, The Netherlands. T.Kleefstra@antrg.umcn.nl
European Journal of Human Genetics : EJHG
|October 16, 2003
Summary
Systematic screening of the MECP2 gene is recommended for females with unexplained intellectual disability and patients with Angelman syndrome features lacking methylation defects. This aids in diagnosing Rett syndrome (RTT) and understanding MECP2 mutation phenotypes.
Area of Science:
- Neurogenetics
- Molecular Diagnostics
- Developmental Disorders
Background:
- Rett syndrome (RTT) is a common neurodevelopmental disorder in females, primarily caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene.
- The clinical presentation of MECP2 mutations is highly variable, affecting both males and females with a wide range of severity.
Purpose of the Study:
- To evaluate the utility of systematic MECP2 gene screening in patients with unexplained mental retardation.
- To further delineate the phenotypic spectrum associated with MECP2 mutations.
Main Methods:
- Mutational analysis of the MECP2 gene was conducted in cohorts of female patients with unexplained mental retardation (negative for FMR1 CGG repeat expansion), and in male and female patients with features suggestive of Angelman or Prader-Willi syndromes without specific methylation defects.
- Specific patient groups included: females negative for Fragile-X testing (N=92), Angelman-negative patients (N=63), and Prader-Willi-negative patients (N=98).
Main Results:
- One nonsense mutation (p.Q406X) was identified in the cohort of females negative for Fragile-X studies.
- Two missense mutations (p.R133C and mosaic p.T158M) associated with classical RTT were found in Angelman-negative patients.
- No pathogenic mutations were detected in the Prader-Willi-negative cohort.
Conclusions:
- MECP2 mutation analysis is supported in patients presenting with Angelman syndrome-like features but lacking chromosome 15q11-q13 methylation defects.
- For other patients with unexplained mental retardation, additional clinical characteristics should guide the decision for MECP2 gene analysis.