LINKAGE AND PHYSICAL MAPPING OF X-LINKED LISSENCEPHALY SBH (XLIS) - AGENE CAUSING NEURONAL MIGRATION DEFECTS IN HUMAN BRAIN/

While disorders of neuronal migration are associated with as much as 2 5% of recurrent childhood seizures, few of the genes required to estab lish neuronal position in cerebral cortex are known. Subcortical band heterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migra tion disorders producing epilepsy and variable cognitive impairment, c an be inherited alone or together in a single pedigree. Here we report a new genetic locus, XLIS, mapped by linkage analysis of five familie s and physical mapping of a balanced X;2 translocation in a girl with LIS. Linkage places the critical region in Xq21-q24, containing the br eakpoint that maps to Xq22.3-q23 by high-resolution chromosome analysi s. Markers used for somatic cell hybrid and fluorescence in situ hybri dization analyses place the XLIS region within a 1 cM interval. These data suggest that SBH and X-linked lissencephaly are caused by mutatio n of a single gene, XLIS, that the milder SBH phenotype in females res ults from random X-inactivation (Lyonization), and that cloning of gen es from the breakpoint region on X will yield XLIS.