Linkage and physical mapping of X-linked lissencephaly/SBH (XLIS): a gene causing neuronal migration defects in human brain

While disorders of neuronal migration are associated with as much as 25% ofrecurrent childhood seizures, few of the genes required to establishneuronal position in cerebral cortex are known. Subcortical bandheterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migrationdisorders producing epilepsy and variable cognitive impairment, can beinherited alone or together in a single pedigree. Here we report a newgenetic locus, XLIS, mapped by linkage analysis of five families andphysical mapping of a balanced X;2 translocation in a girl with LIS.Linkage places the critical region in Xq21-q24, containing the breakpointthat maps to Xq22.3-q23 by high-resolution chromosome analysis. Markersused for somatic cell hybrid and fluorescence in situ hybridizationanalyses place the XLIS region within a 1 cM interval. These data suggestthat SBH and X-linked lissencephaly are caused by mutation of a singlegene, XLIS, that the milder SBH phenotype in females results from randomX-inactivation (Lyonization), and that cloning of genes from the breakpointregion on X will yield XLIS.