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Title: X-inactivation patterns in Aicardi syndrome

Author
item EBLE, T - BAYLOR COLLEGE MED
item FANG, P - BAYLOR COLLEGE MED
item JIN, W - BAYLOR COLLEGE MED
item SUTTON, V - BAYLOR COLLEGE MED
item LEWIS, R - BAYLOR COLLEGE MED
item Van Den Veyver, Ignatia

Submitted to: American Society of Human Genetics
Publication Type: Abstract Only
Publication Acceptance Date: 4/15/2006
Publication Date: 10/9/2006
Citation: Eble, T.N., Fang, P., Jin, W., Sutton, V.R., Lewis, R.A., Van den Veyver, I.B. 2006. X-inactivation patterns in Aicardi syndrome [abstract]. American Society of Human Genetics, 2006 Annual Meeting, October 9-13, 2006, New Orleans, Louisiana. p. 122.

Interpretive Summary:

Technical Abstract: Aicardi syndrome (AIC) is a severe sporadic neurodevelopmental disorder, characterized by a classic triad of agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms. Because nearly all affected individuals are female and the few known males with AIC have a 47,XXY karyotype, it is thought that the condition is caused by mutations in a gene subjected to X inactivation. Previous limited X-inactivation (XI) studies in AIC have had conflicting results. Therefore we studied XI in AIC, determined the parental origin of the inactive allele when skewed and investigated correlation between the severity of the phenotypes and the ratio of XI skewing, which has not been documented previously. The human androgen receptor assay was performed on DNA extracted from peripheral blood leukocytes (PBL) of 18 affected girls and their parents. Samples for this initial study came from girls with AIC who had all features of the classic triad. Phenotypic features of the study participants were confirmed with neurological and ophthalmologic examinations, parental interviews and review of medical records and were recorded in a database. With a cut-off of >70%:30%, the assay determined that 6 of 18 samples (30%) showed skewed patterns of XI. A tendency for skewing (66%:34%) was seen in 1 sample, and 1 sample was uninformative. Of the 4 samples with non-random XI where both parents could be studied, 3 preferentially inactivated the paternally inherited X chromosome. This is consistent with the hypothesis that AIC is caused by de novo X-linked mutations, which primarily arise on the paternal X chromosome. As subjects were selected by their more typical presentation, it was not surprising that we found no correlation between XI patterns and overall phenotypic features. However our data suggest a correlation with non-neurological features. DNA from additional individuals, including those with less severe phenotypes and from two brain samples, will be studied to confirm this and determine the extent of the XI-phenotype correlation. In conclusion, these initial findings support the hypothesis that the mutated gene for AIC is X-linked.