Homozygosity of the Xq13.2q21.1 Region and Specific SNPs Correlates with Nonrandom X Chromosome Inactivation.

Abstract

Background: Nonrandom X chromosome inactivation (XCI) is thought to contribute to symptom expression in female carriers of X-linked diseases, yet the mechanisms remain unclear. This study investigated the relationship between genetic factors on the X chromosome and XCI status.

Methods: We used chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) to analyze five stem cell lines with nonrandom XCI and four with random XCI. We compared copy number variation (CNV), re-gions of homozygosity (ROH), single nucleotide variants (SNVs), and XCI status in these cell lines.

Results: The total number of CNVs and their distribution did not differ significantly between groups. No CNVs larger than 400 kilobase pairs (Kb) on the X chromosome were detected, and no pathogenic CNVs were identified in any of the cell lines. ROH in the Xq13.2q21.1 region was present in four out of five nonrandom XCI cells but was absent in all random XCI cells. Sequencing identified an average of 27.2 and 25 nonsynonymous variants in nonrandom XCI cells and random XCI cells, respectively. Nine SNPs were specific to the X chromosome in non-random XCI cells, whereas one unique SNP was detected in random but not in nonrandom XCI cells.

Conclusions: Homozygosity in the Xq13.2q21.1 region and specific SNPs may be associated with nonrandom XCI status, suggesting a potential genetic basis for XCI patterns.