Intellectual disability (ID) affects 30% more males than females. This sex bias can be attributed to the enrichment of genes on the X chromosome playing essential roles in the central nervous system and their hemizygous state on males. Moreover, as a result of X chromosome inactivation (XCI), most genes on one of the X chromosomes in female somatic cells are epigenetically silenced, so that females carrying X-linked variants are not expected to be so severely affected as males. Consequently, the knowledge about X-linked ID (XLID) in females is still scarce. Herein, we used extreme XCI skewing (≥ 90%) to predict X-linked variants in females with idiopathic ID. XCI profiles from 53 probands were estimated from blood and buccal mucosa through a methylation-sensitive AR/RP2 assay. DNA samples with extreme XCI skewing were then submitted to array-comparative genomic hybridization and whole-exome sequencing. Seven females (13.2%) exhibited extreme XCI skewing, a percentage significantly higher than expected for healthy females in our population. XLID-potentially related variants were identified in five patients with extreme XCI skewing, including one pathogenic rstructural rearrangement [der(X) chromosome from a t(X;2)] and four single nucleotide variants in NLGN4X, HDAC8, TAF1, and USP9X genes, two of which affecting XCI escape genes. XCI skewing showed to be an outstanding approach for the characterization of molecular mechanisms underlying XLID in females. Beyond expanding the spectrum of variants/phenotypes associated with ID, our results pointed to compensatory biological pathways underlying XCI and uncover new insights into the involvement of escape genes on XLID, impacting genetic counseling.

智力障碍（ID）对男性的影响比对女性的影响多30％。这种性别偏见可归因于X染色体上基因的富集，这些基因在中枢神经系统中发挥着重要作用，并且在男性中处于半合子状态。此外，由于X染色体失活（XCI），雌性体细胞中X染色体之一上的大多数基因在表观遗传上均被沉默，因此携带X连锁变体的雌性不会像雄性那样受到严重影响。因此，关于女性中X连锁ID（XLID）的知识仍然很少。本文中，我们使用极端XCI偏斜（≥90％）来预测具有特发性ID的女性的X连锁变异。通过对甲基化敏感的AR / RP2从血液和颊粘膜中评估了53个先证者的XCI谱分析。然后将具有极端XCI偏斜的DNA样品进行阵列比较基因组杂交和全外显子组测序。七名女性（13.2％）表现出极高的XCI偏斜，这一百分比显着高于我们人口中健康女性的预期。在5例XCI严重偏斜患者中鉴定出与XLID潜在相关的变异，包括1个病原体结构重排[at（X; 2）的der（X）染色体]和NLGN4X，HDAC8，TAF1和USP9X的4个单核苷酸变异基因，其中两个影响XCI逃逸基因。XCI偏斜被证明是表征女性XLID潜在分子机制的杰出方法。除了扩大与ID相关的变体/表型的范围外，我们的结果还指出了XCI的补偿性生物途径，并揭示了逃逸基因参与XLID的新见解，从而影响了遗传咨询。