American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:728–734 (2007) Dysregulation of X-Linked Gene Expression in Klinefelter’s Syndrome and Association With Verbal Cognition

Klinefelter’s Syndrome (KS) is a chromosomal karyotype with one or more extra X chromosomes. KS individuals often show language impairment and the phenotype might be due to overexpression of genes on the extra X chromosome(s). We profiled mRNA derived from lymphoblastoid cell lines from males with documented KS and control males using the Affymetrix U133P microarray platform. There were 129 differentially expressed genes (DEGs) in KS group compared with controls after Benjamini–Hochberg false discovery adjust-ment. The DEGs included 14 X chromosome genes which were significantly over-represented. The Y chromosome had zero DEGs. In exploratory ana-lysis of gene expression–cognition relationships, 12 DEGs showed significant correlation of expres-sion with measures of verbal cognition in KS. Overexpression of one pseudoautosomal gene, GTPBP6 (GTP binding protein 6, putative) was inversely correlated with verbal IQ (r0.86, P<0.001) and four other measures of verbal ability. Overexpression of XIST was found in KS compared to XY controls suggesting that silencing of many genes on the X chromosome might occur in KS similar to XX females. The microarray findings for eight DEGs were validated by quanti-tative PCR. The 14 X chromosome DEGs were not differentially expressed in prior studies compar-ing female and male brains suggesting a dysregu-lation profile unique to KS. Examination of X-linked DEGs, such as GTPBP6, TAF9L, and CXORF21, that show verbal cognition–gene expression correlations may establish a causal link between these genes, neurodevelopment, and language function. A screen of candidate genes may serve as biomarkers of KS for early diagnosis. 2007 Wiley-Liss, Inc