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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234607 | GEO | 2024/04/24

REPOSITORIES: GEO

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Project description:X chromosome inactivation (XCI) is a dosage compensation mechanism in female cells to regulate X-linked gene expression. We report here that subcultures from established lines of female hESCs displayed variations (0-100%) in the expression of XCI markers such as XIST RNA coating and enrichment of histone H3 lysine 27 trimethylation (H3K27me3) on inactive X chromosome. Surprisingly, regardless of the presence or absence of XCI markers in different cultures, all female hESCs we examined (H7, H9, and HSF6 cells) exhibit a mono-allelic expression pattern for a majority of X-linked genes. Our results suggest that these established female hESCs have completed XCI during the process of derivation and/or propagation, and the XCI pattern of lines we investigated is already non-random. However, XIST gene expression in subsets of female hESCs is unstable and subject to epigenetic silencing through DNA methylation. Concomitant with the loss of XCI markers including XIST expression and H3K27me3, approximately 12% of X-linked CpG islands become hypomethylated and a subset of previously silenced X-linked alleles are reactivated, resulting a significant elevation of gene expression dosage. Because changes in dosage compensation of X-linked genes could impair somatic cell function, we propose that XCI status should be routinely checked in subcultures of female hESCs, with cultures displaying XCI markers better suited for use in regenerative medicine. Keywords: Genotyping, gene expression and DNA methylation We used Affymetrix Genotyping array for looking for X-linked SNPs with HSF6, H7 and H9 genomic DNA, Agilent Gene expression array for comparing gene expression patten changes between HSF6 hESCs with X-inactiation and HSF6 hESCs without X-inactivation (3 repeats). Finally, mDIP-Chip method was used to detect X-linked CpG island methylation changes differences between hESCs with X-inactivation and hESCs without X-inactivation using Agilent CpG island array (3 repeats, and one of them has dye swap)

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

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