Rett syndrome (MIM 312750) is a neurodevelopmental disorder of unknown cause that primarily affects girls (Naidu 1997). The clinical picture is enigmatic for the normal perinatal period, followed by rapid deceleration of head growth during early childhood, with loss of purposeful hand movements and apraxia. Approximately 99.5% of cases are isolated, with no other affected relative. The mode of inheritance has been hotly debated, with models of both X-linked and sex-influenced autosomal inheritance advanced to explain the preponderance of isolated female cases. We describe a family with the largest number of female siblings affected with Rett syndrome identified to date, and we have used data from this family, as well as from families previously described (Ellison et al. 1992; Schanen et al. 1997; Xiang et al. 1998), to demonstrate X-linked dominant inheritance and to localize the responsible locus to Xq28. A Brazilian family presented with three daughters showing clinical features characteristic of Rett syndrome. All three affected children showed rapid deceleration of head growth, with subsequent progressive mental deterioration. Two of them (individuals II-6 and II-7; fig. 1A) were examined at the Kennedy Krieger Institute. The two living affected daughters (II-6 and II-7), who were examined at 9 and 5½ years of age, showed no purposeful hand movements, with persistent hand stereotypes and rubbing of the torso. They showed spontaneous episodes of hyperventilation while awake. They had a severe attention deficit and no language development. They had significant muscle wasting and an inability to walk. Both had intellectual and adaptive behavior at the 1–6-mo level. Although the younger daughter (II-7) still was able to reach for food, she was without other purposeful hand use. She also had marked air swallowing, with abdominal bloating. DNA was collected for genetic analyses of these two affected girls, their parents, an additional affected sister (II-5), who subsequently died at 12 years of age, and two normal female siblings. To determine whether this family was consistent with X-linked dominant maternal inheritance, we genotyped the five sisters and their parents for 47 polymorphic markers distributed throughout the X chromosome (fig. 1). Markers were selected from the Genome Database so as to obtain informative markers spaced apart at a maximum distance of 10 cM. Phase was established unambiguously in the mother, and each maternal meiotic breakpoint was mapped for each daughter (fig. 1A). Concordance analysis showed that only Xq28 was shared among the three affected girls. This same region was not shared with the unaffected sisters.

We then used the genotype data to conduct a multipoint linkage analysis of the Brazilian family. The relative order of microsatellite markers along the X chromosome and their genetic distances (in centimorgans) were derived from published maps (Fain et al. 1995), by use of a model of X-linked dominant inheritance with the mother assigned the status “nonpenetrant carrier”(fig. 2A). The GENEHUNTER package (Kruglyak et al. 1996) was used for multipoint linkage analyses across the entire X chromosome. Only the Xq28 region of the X chromosome showed a positive LOD score (Z; fig. 2A). The threshold for statistically significant 1.2 evidence of linkage of X-linked traits is. Al-Z 1 2.0 though the Xq28 region did not reach this threshold, the majority of the remainder of the X chromosome showed. Thus, the statistical difference (Ko-Z! 1.0 bayashi et al. 1995) between Xq28 and the majority of the remainder of the X chromosome was 12. 0, lending some statistical support to the results of the …