Rett syndrome: potential gene sources ‐ phenotypical variability

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Abstract
A previous genealogic study on classical Swedish Rett syndrome (RS) females documented an increased rate of common ancestry, with a high percentage originating generations ago in the same homestead. The present study, an a priori test of the first study, examines an additional 20 RS females, who were consecutively traced. Of these, no fewer than 10/19 (53%) originated from earlier defined "Rett areas": 11/19 (58%) could even be traced to the same homestead. In two clusters, each consisting of three RS females, all six subjects were descendants of the same two couples several generations ago. Consanguineous marriages among grandparents on both sides were found to have occurred in 11% (4/37), i.e. significantly more frequently than in the average Swedish population (1%). The results of this second study confirm all points of the first. A clinical analysis of cases with common ancestral origin underlines the phenotypical variability which is often seen in interrelated RS females. We conclude that RS can appear in either its classical form or as a variant. Our genealogical data may indicate transmission starting with a premutation that over generations can result in a full mutation, probably when the parents have the premutation in a homozygous form.