The genetics of Rett syndrome: the consequences of a disorder where every case is a new mutation.

The genetic data on Rett syndrome suggest a mutant gene acting as an X-linked dominant with lethality in the male and reproductive lethality in the female. Thus, all cases represent new mutations. The presence of two affected sisters in two of 600 families indicates the ratio of germinal mosaicism to all germinal mutants is about 1:150. After excluding propositi, a 1:1 M:F ratio of other siblings would be expected and there should be an increase in spontaneous abortion only in the germinal mosaicism families. The presence of two abortions at three months gestation in such a family suggest the Rett syndrome protein is essential to brain development at this stage of embryogenesis. Neuropathological and two-dimensional gel electrophoretic examination of the brains of aborted male fetuses in such families should provide critical evidence on the pathogenesis of the disease. Classical linkage studies cannot be done. The most parsimonious method of locating the site of the Rett syndrome gene is to do high resolution banding in all Rett syndrome cases, searching for X-chromosome deletions, or less likely, X:autosome translocations.