Non-random X chromosome inactivation in Aicardi syndrome

Abstract

Most females have random X-chromosome inactivation (XCI), defined as an equal likelihood for inactivation of the maternally- or paternally-derived X chromosome in each cell. Several X-linked disorders have been associated with a higher prevalence of non-random XCI patterns, but previous studies on XCI patterns in Aicardi syndrome were limited by small numbers and older methodologies, and have yielded conflicting results. We studied XCI patterns in DNA extracted from peripheral blood leukocytes of 35 girls with typical Aicardi syndrome (AIC) from 0.25 to 16.42 years of age, using the human androgen receptor assay. Data on 33 informative samples showed non-random XCI in 11 (33%), defined as a >80:20% skewed ratio of one versus the other X chromosome being active. In six (18%) of these, there was a >95:5% extremely skewed ratio of one versus the other X chromosome being active. XCI patterns on maternal samples were not excessively skewed. The prevalence of non-random XCI in Aicardi syndrome is significantly different from that in the general population (p < 0.0001) and provides additional support for the hypothesis that Aicardi syndrome is an X-linked disorder. We also investigated the correlation between X-inactivation patterns and clinical severity and found that non-random XCI is associated with a high neurological composite severity score. Conversely, a statistically significant association was found between random XCI and the skeletal composite score. Correlations between X-inactivation patterns and individual features were made and we found a significant association between vertebral anomalies and random XCI.

Figure 1. Patterns of X chromosome inactivation in girls with Aicardi syndrome and their mothers

The % XCI is shown for each AIC girl (a) and for mother-girl pairs (b). a includes only 33 bars because two of the 35 girls tested had non-informative results. Twenty-five mother-girl pairs for which informative results were available for both mother and daughter are included in b. The active % of one versus the other X-chromosome is represented as black-and-white vertical bars for AIC girls and as black-and-grey vertical bars for mothers. The areas on the graphs below the hatched line delineate the 80:20% cut off for skewing. Asterisks indicate pairs in which the mother has skewed XCI while the daughter has random XCI. Dagger indicates a pair in which both mother and daughter have extremely skewed XCI