Segregation of a totally skewed pattern of X chromosome inactivation in four familial cases of Rett syndrome without MECP2 mutation: implications forthe disease

Background-Rett syndrome is a neurodevelopmental disorder affecting only gi rls; 99.5% of Rett syndrome cases are sporadic, although several familial c ases have been reported. Mutations in the MECP2 gene were identified in app roximately 70-80% of sporadic Rett syndrome cases. Methods-We have screened the MECP2 gene coding region for mutations in five familial cases of Rett syndrome and studied the patterns of X chromosome i nactivation (XCI) in each girl. Results-We found a mutation in MECP2 in only one family. In the four famili es without mutation in MECP2, we found that (1) all mothers exhibit a total ly skewed pattern of XCI; (2) six out of eight affected girls also have a t otally skewed pattern of XCI; and (3) it is the paternally inherited X chro mosome which is active in the patients with a skewed pattern of XCI. Given that the skewing of XCI is inherited in our families, we genotyped the whol e X chromosome using 32 polymorphic markers and we show that a locus potent ially responsible for the skewed XCI in these families could be located on the short arm of the X chromosome. Conclusion-These data led us to propose a model for familial Rett syndrome transmission in which two traits are inherited, an X linked locus abnormall y escaping X chromosome inactivation and the presence of a skewed XCI in ca rrier women.