Rett syndrome is a neurodevelopmental disorder affecting 1 in 10,000-15,000 females worldwide. Apparently normal at birth, girls with Rett syndrome undergo developmental regression and acquire a neurologic and behavioral profile which has been used to define diagnostic criteria for the disorder. Although Rett syndrome generally occurs sporadically rare familial recurrences indicate a genetic basis for the disorder. Several features are consistent with an X-linked dominant locus including: (1) the exclusive occurrence of the classic phenotype in females; (2) the identification of severely affected males in Rett syndrome kindreds; (3) mother to daughter transmission; and (4) non-random X-chromosome inactivation patterns in nonmanifesting obligate carrier females. Exclusion mapping data from these rare families with recurrent Rett syndrome localize the gene to the distal long am of the X chromosome (Xq27.3-Xqter). The focus of this proposal is the identification of the causative gene using combined molecular and cytogenetic approaches. Based on their previous work and the milieu and resources of the new Human Genetics department at UCLA, they are in an excellent position to perform these studies. The investigations will test three primary hypotheses using combined molecular and cytogenetic approaches.
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