Somatic mosaicism and variable penetrance in doublecortin-associated migration disorders

Area of Science:

• Neurogenetics
• Developmental Neuroscience
• Human Genetics

Background:

• X-linked isolated lissencephaly sequence (XLIS) and subcortical band heterotopia (SBH) are related brain malformations.
• These disorders stem from mutations in the doublecortin (DCX) gene.

Purpose of the Study:

• To identify novel mutations in the DCX gene associated with XLIS and SBH.
• To investigate the occurrence and implications of somatic mosaicism in these allelic disorders.
• To assess the variability in clinical presentation and penetrance, including in heterozygous carriers.

Main Methods:

• Genetic analysis of DNA samples from seven families affected by XLIS/SBH.
• Mutation screening of the DCX gene.
• Clinical evaluation of affected individuals to assess phenotype and penetrance.

Main Results:

• Four previously undiscovered mutations in the DCX gene were identified.
• A high frequency of somatic mosaicism was observed in both male and female patients.
• Variable expressivity and incomplete penetrance of bilateral SBH were noted, including non-penetrance in a heterozygous female.
• Prenatal diagnosis was successfully performed in one family.

Conclusions:

• Mutations in the DCX gene are a significant cause of XLIS and SBH.
• Somatic mosaicism and variable penetrance are crucial factors influencing the phenotype and inheritance of these disorders.
• Genetic counseling and prenatal diagnosis are important for families with a history of DCX-related brain malformations.