A Rett syndrome patient with a ring X chromosome: further evidence for skewing of X inactivation and heterogeneity in the aetiology of the disease

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, characteris ed by regression of development in young females. Recently, mutations in th e 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 th e pattern of X chromosome inactivation (XCI) relates to the penetrance of R TT; 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. Fur ther, no mutations were found in the MECP2 gene present on the intact X. Ou r data, in conjunction with two previously published cases of X chromosome abnormalities in RTT, indicate that X chromosome rearrangements are sporadi cally associated with RTT in conjunction with extreme skewing of X inactiva tion. Based on our case and reported data, we discuss the evidence for a se cond X-linked locus for RTT associated with lower penetrance, and a differe nt 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 majorit y of familial cases that are negative for MECP2 mutations.