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 adjustment. The DEGs included 14 X 
chromosome genes which were significantly over-represented. The Y chromosome had 
zero DEGs. In exploratory analysis of gene expression-cognition relationships, 
12 DEGs showed significant correlation of expression with measures of verbal 
cognition in KS. Overexpression of one pseudoautosomal gene, GTPBP6 (GTP binding 
protein 6, putative) was inversely correlated with verbal IQ (r = -0.86, 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 quantitative PCR. The 14 X chromosome 
DEGs were not differentially expressed in prior studies comparing female and 
male brains suggesting a dysregulation 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.