No abstract

Investigação de desvios extremos da inativação do cromossomo X em mulheres com deficiência intelectual idiopática como indicativo de variantes

Intellectual disability (ID) is an early onset impairment in cognitive functioning and adaptive behavior, affecting approximately 1% of the population worldwide. Extreme deviations of X-chromosome inactivation (XCI) can be related to ID phenotypes caused by pathogenic variants in the X-chromosome. We analyzed the blood pattern of XCI in 194 women with idiopathic ID, using the androgen receptor gene (AR) methylation assay. Among the 136 patients who were informative, 11 patients (8%) presented with extreme or total XCI deviation (≥90%), which was signi cantly higher than the deviation expected by chance. Whole-exome data obtained from these 11 patients revealed the presence of dominant pathogenic variants in eight of them, all sporadic cases, resulting in a molecular diagnosis rate of 73%. All variants were mapped to ID-related genes with dominant phenotypes: four variants in the X-linked genes DDX3X (two patients), WDR45 and PDHA1), of which one is an XCI escape gene (DDX3X), and four variants in autosomal genes (KCNB1, CTNNB1, YY1, ANKRD11). Three of the autosomal genes had no obvious correlation with the observed XCI skewing. However, YY1 is a known transcriptional repressor that acts in the binding of the XIST long noncoding RNA on the inactive X chromosome, providing a mechanistic link between the pathogenic variant and the detected skewed XCI in the carrier. These data con rm that extreme XCI skewing in females with ID is highly indicative of causative X-linked pathogenic variants and point to the possibility of identifying causative variants in autosomal genes with a role in XCI.

Intellectual disability (ID) is an early onset impairment in cognitive functioning and adaptive behavior, affecting approximately 1% of the population worldwide. Extreme deviations of X-chromosome inactivation (XCI) can be related to ID phenotypes caused by pathogenic variants in the X-chromosome. We analyzed the blood pattern of XCI in 194 women with idiopathic ID, using the androgen receptor gene (AR) methylation assay. Among the 136 patients who were informative, 11 patients (8%) presented with extreme or total XCI deviation (≥90%), which was significantly higher than the deviation expected by chance. Whole-exome data obtained from these 11 patients revealed the presence of dominant pathogenic variants in eight of them, all sporadic cases, resulting in a molecular diagnosis rate of 73%. All variants were mapped to ID-related genes with dominant phenotypes: four variants in the X-linked genes DDX3X (two patients), WDR45 and PDHA1), of which one is an XCI escape gene (DDX3X), and four variants in autosomal genes (KCNB1, CTNNB1, YY1, ANKRD11). Three of the autosomal genes had no obvious correlation with the observed XCI skewing. However, YY1 is a known transcriptional repressor that acts in the binding of the XIST long noncoding RNA on the inactive X chromosome, providing a mechanistic link between the pathogenic variant and the detected skewed XCI in the carrier. These data confirm that extreme XCI skewing in females with ID is highly indicative of causative X-linked pathogenic variants and point to the possibility of identifying causative variants in autosomal genes with a role in XCI.