Molecular diagnostic dilemmas in Rett syndrome

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Rett syndrome (RTT) is a progressive, X-linked neurodevelopmental disorder.
• Mutations in the MECP2 gene on chromosome Xq28 cause RTT.
• RTT typically presents after 6-18 months of normal development with loss of acquired skills.

Purpose of the Study:

• To identify MECP2 gene variants in patients with RTT or unexplained intellectual disability.
• To investigate genotype-phenotype correlations for novel and non-recurrent MECP2 mutations.

Main Methods:

• Bidirectional sequencing of the MECP2 gene's open reading frame.
• Diagnostic testing of 30 patients with RTT or unexplained intellectual disability.
• Family studies for genotype-phenotype correlation analysis.

Main Results:

• Twenty different MECP2 variants were identified in 30 patients.
• Twelve missense, four nonsense, two deletion, and two frameshift mutations were found.
• Seven novel mutations were identified: E137_L386del, K192X, S291QfsX26, G343AfsX6, I293_S350del, P384L, and A443T.

Conclusions:

• Diagnostic testing identified various MECP2 alterations in patients with RTT or unexplained intellectual disability.
• Family studies are crucial for interpreting the significance of MECP2 variants.
• The complexity of MECP2 alterations necessitates careful genotype-phenotype correlation for accurate diagnosis.