title: A Rett syndrome patient with a ring X chromosome: further evidence for skewing of X inactivation and heterogeneity in the aetiology of the disease.
abstract: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, characterised by regression of development in young females. Recently, mutations in the MECP2 gene were found to be present in 80% of sporadic cases, but in much lower frequency (< 30%) among familial cases. Several reports claim that the pattern of X chromosome inactivation (XCI) relates to the penetrance of RTT; in some cases skewed XCI is seen in Rett patients, and in others it is observed among normal carriers. We present here a case of RTT with a 46,X,r(X) in which complete skewed inactivation of the ring was demonstrated. Further, no mutations were found in the MECP2 gene present on the intact X. Our data, in conjunction with two previously published cases of X chromosome abnormalities in RTT, indicate that X chromosome rearrangements are sporadically associated with RTT in conjunction with extreme skewing of X inactivation. Based on our case and reported data, we discuss the evidence for a second X-linked locus for RTT associated with lower penetrance, and a different pattern of XCI, than for MECP2. This would result in a larger proportion of phenotypically normal carrier women transmitting the mutation for this putative second locus, and account for the minority of sporadic and majority of familial cases that are negative for MECP2 mutations.
authors: Laboratory of Cytochemistry and Cytometry, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. c.rosenberg@lumc.nl
authors: C
authors: C
authors: Rosenberg
authors: C H
authors: CH
authors: Wouters
authors: K
authors: K
authors: Szuhai
authors: R
authors: R
authors: Dorland
authors: P
authors: P
authors: Pearson
authors: B T
authors: BT
authors: Poll-The
authors: R M
authors: RM
authors: Colombijn
authors: M
authors: M
authors: Breuning
authors: D
authors: D
authors: Lindhout
mesh_terms: D004303:Dosage Compensation, Genetic; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D009154:Mutation; D015518:Rett Syndrome / Q000235:genetics*; D012303:Ring Chromosomes; D014960:X Chromosome