title: Studies of X inactivation and isodisomy in twins provide further evidence that the X chromosome is not involved in Rett syndrome.
abstract: Rett syndrome (RS), a progressive encephalopathy with onset in infancy, has been attributed to an X-linked mutation, mainly on the basis of its occurrence almost exclusively in females and its concordance in female MZ twins. The underlying mechanisms proposed are an X-linked dominant mutation with male lethality, uniparental disomy of the X chromosome, and/or some disturbance in the process of X inactivation leading to unequal distributions of cells expressing maternal or paternal alleles (referred to as a "nonrandom" or "skewed" pattern of X inactivation). To determine if the X chromosome is in fact involved in RS, we studied a group of affected females including three pairs of MZ twins, two concordant for RS and one uniquely discordant for RS. Analysis of X-inactivation patterns confirms the frequent nonrandom X inactivation previously observed in MZ twins but indicates that this is independent of RS. Analysis of 29 RS females reveals not one instance of uniparental X disomy, extending the observations previously reported. Therefore, our findings contribute no support for the hypothesis that RS is an X-linked disorder. Furthermore, the concordant phenotype in most MZ female twins with RS, which has not been observed in female twins with known X-linked mutations, argues against an X mutation.
authors.affiliation: Center for Medical Genetics, Johns Hopkins University, Baltimore, MD.
authors.forename: B R
authors.initials: BR
authors.lastname: Migeon
authors.forename: M A
authors.initials: MA
authors.lastname: Dunn
authors.forename: G
authors.initials: G
authors.lastname: Thomas
authors.forename: B J
authors.initials: BJ
authors.lastname: Schmeckpeper
authors.forename: S
authors.initials: S
authors.lastname: Naidu
mesh_terms: D002648:Child; D002869:Chromosome Aberrations; D004200:Diseases in Twins / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D010375:Pedigree; D015518:Rett Syndrome / Q000235:genetics*; D014430:Twins, Monozygotic; D014960:X Chromosome