doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH)

Subcortical laminar heterotopia (SCLH), or 'double cortex', is a corticaldysgenesis disorder associated with a defect in neuronal migration.Clinical manifestations are epilepsy and mental retardation. This disorder,which mainly affects females, can be inherited in a single pedigree withlissencephaly, a more severe disease which affects the male individuals.This clinical entity has been described as X- SCLH/LIS syndrome. Recentlywe have demonstrated that the doublecortin gene, which is localized on theX chromosome, is implicated in this disorder. We have now performed asystematic mutation analysis of doublecortin in 11 unrelated females withSCLH (one familial and 10 sporadic cases) and have identified mutations in10/11 cases. The sequence differences include nonsense, splice site andmissense mutations and these were found throughout the gene. These resultsprovide strong evidence that loss of function of doublecortin is the majorcause of SCLH. The absence of phenotype-genotype correlations suggests thatX-inactivation patterns of neuronal precursor cells are likely tocontribute to the variable clinical severity of this disorder in females.