MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that apparen tly is lethal in male embryos. RTT almost exclusively affects female offspr ing and, in 99.5% of all cases, is sporadic and due to de novo mutations in the MECP2 gene. Familial cases of RTT are rare and are due to X-chromosoma l inheritance from a carrier mother. We analyzed the parental origin of MEC P2 mutations in sporadic cases of RTT, by analysis of linkage between the m utation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and we found a high predominance of mutations of pate rnal origin in 26 of 27 cases (P < .001). The paternal origin was independe nt of type of mutation and was found for single-base exchanges as well as f or deletions. Parents were not of especially advanced age. We conclude that de novo mutations in RTT occur almost exclusively on the paternally derive d X chromosome and that this is most probably the cause for the high female : male ratio observed in patients with RTT. Affected males recently have be en described in a few cases of familial inheritance. Identification of the parental origin may be useful to distinguish between the sporadic form of R TT and a potentially familial form. This distinction will allow geneticists to offer more-specific counseling and discriminate between higher (materna l origin) and lower (paternal origin) recurrence risk.