A NEW RETT-SYNDROME FAMILY CONSISTENT WITH X-LINKED INHERITANCE EXPANDS THE X-CHROMOSOME EXCLUSION MAP

Although familial recurrences of Rett syndrome (RTT) comprise only sim ilar to 1% of the reported cases, it is these cases that hold the key for the understanding of the genetic basis of the disorder. Families i n which RTT occurs in mother and daughter, aunt and niece, and half si sters are consistent with dominant inheritance and variable expressivi ty of the phenotype. Recurrence of RTT in sisters is likely due to ger m-line mosaicism in one of the parents, rather than to recessive inher itance. The exclusive occurrence of classic RTT in females led to the hypothesis that it is X-linked and may be lethal in males. In an X-lin ked dominant disorder, unaffected obligate-carrier females would be ex pected to show nonrandom or skewed inactivation of the X chromosome be aring the mutant allele, We investigated the X chromosome inactivation (XCI) patterns in the female members of a newly identified family wit h recurrence of RTT in a maternal aunt and a niece. Skewing of XCI is present in the obligate carrier in this family, supporting the hypothe sis that RTT is an X-linked disorder. However, evaluation of the XCI p attern in the mother of affected half sisters shows random XCI, sugges ting germ-line mosaicism as the cause of repeated transmission in this family. To determine which regions of the X chromosome were inherited concordantly/discordantly by the probands, we genotyped the individua ls in the aunt-niece family and two previously reported pairs of half sisters. These combined exclusion-mapping data allow us to exclude the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. This represents an extension of the previous exclusion map.