Identification of skewed X chromosome inactivation using exome and transcriptome sequencing in patients with suspected rare genetic disease

Purpose: Evaluation of XCI status in a cohot of female patients with suspected rare genetic diseases using exome and RNA sequencing Results: We developed a method for estimating X inactivation status, using exome and transcriptome sequencing data from 112 female samples. We built a reference model for evaluation of XCI in 135 females from the GTEx consortium. We tested and validated the model on 14 female individuals with different types of undiagnosed rare genetic disorders who were clinically tested for X-skew using the AR gene assay and compared results to our outlier-based analysis technique. In comparison to the AR clinical test for identification of X inactivation, our method was concordant with AR method in 9 samples, discordant in 3, and provided measures of X inactivation in 2 samples with uninformative clinical results. We applied this method on an additional 98 females presenting to the clinic with phenotypes consistent with different hereditary disorders without a known genetic diagnosis. Here we show the use of transcriptome sequencing data to provide an accurate and complete estimation of X-inactivation and skew status in female patients.