Variable phenotypic expression of a MECP2 mutation in a family

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting females.
• Mutations in the Methyl CpG binding protein 2 (MECP2) gene are the main cause of RTT.
• X chromosome inactivation (XCI) plays a role in the variable expressivity of MECP2 mutations in females.

Purpose of the Study:

• To investigate the genetic basis and clinical presentation of Rett syndrome in a multi-generational family.
• To understand the role of X chromosome inactivation (XCI) in the phenotypic variability of MECP2 mutations.
• To highlight diagnostic challenges in carrier females with mild or borderline cognitive function.

Main Methods:

• Genetic analysis to identify mutations in the MECP2 gene.
• Clinical evaluation of affected individuals and carrier females.
• Assessment of X chromosome inactivation patterns.

Main Results:

• A 44 bp deletion (1164-1207del44) in the MECP2 gene was identified in five family members.
• Clinical presentation ranged from classic RTT in one female to milder, progressive neurological involvement (including dystonia) in males and two carrier females.
• Transmitting females exhibited unbalanced XCI, leading to minimal or no RTT features.

Conclusions:

• MECP2 gene deletions can cause a spectrum of neurodevelopmental phenotypes, including atypical Rett syndrome.
• Unbalanced XCI in carrier females can mask the full effects of MECP2 mutations, complicating carrier identification.
• Diagnostic strategies must consider affected offspring to accurately identify MECP2 mutation carriers with subtle cognitive impairments.