Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern

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Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%;P= 0.029). Whole-exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genesDDX3X,NHS,WDR45,MECP2, andSMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected inMED12,HDAC8, andTAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients.

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