Skewed X-chromosome Inactivation in Women with Idiopathic Intellectual Disability is Indicative of Pathogenic Variants

• Published in: Molecular neurobiology Vol. 60; no. 7; pp. 3758 - 3769
• Main Authors: Chaves, Luiza D., Carvalho, Laura M. L., Tolezano, Giovanna C., Pires, Sara F., Costa, Silvia S., de Scliar, Marília O., Giuliani, Liane de R., Bertola, Debora R., Santos-Rebouças, Cíntia B., Seo, Go Hun, Otto, Paulo A., Rosenberg, Carla, Vianna-Morgante, Angela M., Krepischi, Ana C. V.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.07.2023; Springer Nature B.V
• Subjects: Androgen receptors; Biomedical and Life Sciences; Biomedicine; Carrier Proteins - genetics; Cell Biology; Chromosomes; Cognitive ability; DNA methylation; Female; Genes; Genes, X-Linked; Humans; Intellectual disabilities; Intellectual Disability - genetics; Neurobiology; Neurology; Neurosciences; Original Article; Phenotype; Phenotypes; X Chromosome Inactivation - genetics; X chromosomes; X-chromosome inactivation; Intellectual disability; X-chromosome skewing; Escape gene; X-chromosome inactivation; YY1
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-023-03311-0

Intellectual disability (ID) is an early onset impairment in cognitive functioning and adaptive behavior, affecting approximately 1% of the population worldwide. Extreme skewing of X-chromosome inactivation (XCI) can be associated with ID phenotypes caused by pathogenic variants in the X chromosome. We analyzed the XCI pattern in blood samples of 194 women with idiopathic ID, using the androgen receptor gene ( AR ) methylation assay. Among the 136 patients who were informative, 11 (8%) presented with extreme or total XCI skewing (≥ 90%), which was significantly higher than 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 diagnostic rate of 73% (8/11 patients). All variants were mapped to ID-related genes with dominant phenotypes: four variants in the X-linked genes DDX3X (an XCI escape gene; two cases), WDR45, and PDHA1 , and four variants in the autosomal genes KCNB1, CTNNB1, YY1 , and 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 XCI role.