Klinefelter syndrome (KS) displays a broad dysmorphological, endocrinological, and neuropsychological clinical spectrum. We hypothesized that the neurocognitive dysfunction present in KS relies on an imbalance in X-chromosome gene expression. Thus, the X-chromosome inactivation (XCI) pattern and neurocognitive X-linked gene expression were tested and correlated with intelligence quotient (IQ) scores. We evaluated 11 KS patients by (a) IQ assessment, (b) analyzing the XCI patterns using both HUMARA and ZDHHC15 gene assays, and (c) blood RT-qPCR to investigate seven X-linked genes related to neurocognitive development (GTPBP6, EIF2S3, ITM2A, HUWE1, KDM5C, GDI1, and VAMP7) and XIST in comparison with 14 (male and female) controls. Considering IQ 80 as the standard minimum reference, we verified that the variability in IQ scores in KS patients seemed to be associated with the XCI pattern. Seven individuals in the KS group presented a random X-inactivation (RXI) and lower average IQ than the four individuals who presented a skewed X-inactivation (SXI) pattern. The evaluation of gene expression showed higher GTPBP6 expression in KS patients with RXI than in controls (p = 0.0059). Interestingly, the expression of GTPBP6 in KS patients with SXI did not differ from that observed in controls. Therefore, our data suggest for the first time that GTPBP6 expression is negatively associated with full-scale IQ under the regulation of the type of XCI pattern. The SXI pattern may regulate GTPBP6 expression, thereby dampening the impairment in cognitive performance and playing a role in intelligence variability in individuals with KS, which warrants further mechanistic investigations.

Klinefelter 综合征 (KS) 表现出广泛的畸形、内分泌和神经心理学临床谱。我们假设 KS 中存在的神经认知功能障碍依赖于 X 染色体基因表达的不平衡。因此，测试了 X 染色体失活 (XCI) 模式和神经认知 X 连锁基因表达，并将其与智商 (IQ) 分数相关联。我们通过 (a) IQ 评估，(b) 使用 HUMARA 和ZDHHC15 基因检测，以及 (c) 血液 RT-qPCR 以研究与神经认知发育相关的七个 X 连锁基因（GTPBP6, EIF2S3, ITM2A, HUWE1, KDM5C, GDI1， 和 鞋面7） 和 XIST与 14 个（男性和女性）对照相比。将 IQ 80 作为标准的最低参考值，我们验证了 KS 患者 IQ 分数的变异性似乎与 XCI 模式相关。KS 组中的 7 个人表现出随机 X 失活 (RXI) 和比表现出偏斜 X 失活 (SXI) 模式的四个人更低的平均智商。基因表达的评价显示更高GTPBP6 RXI KS 患者的表达高于对照组（磷= 0.0059）。有趣的是，表达式GTPBP6在患有 SXI 的 KS 患者中，与在对照组中观察到的没有差异。因此，我们的数据首次表明GTPBP6在 XCI 模式类型的调节下，表达与全量程 IQ 呈负相关。SXI 模式可以调节GTPBP6 表达，从而抑制认知能力受损并在 KS 个体的智力变异中发挥作用，这需要进一步的机制研究。