Dataset from TRiXi: A Multi-Target Tandem Repeat-Based Method for Accurate Detection of X-Inactivation Skewing in Humans

Dataset from Dóra Goldmann, Björn Gylemo, Maike Bensberg, Ingela Johansson, Svenja Löffert, Júlia Goldmann, Lisa Haglund, Magdalena Vitkova, Janos Kondri, Sandra Hellberg, Engla Haglund, Shadi Jafari, Johnny Ludvigsson, Colm E. Nestor. TRiXi: A Multi-Target Tandem Repeat-Based Method for Accurate Detection of X-Inactivation Skewing in Humans medRxiv 2025.11.24.25340860; doi: https://doi.org/10.1101/2025.11.24.25340860 All data in this dataset are classified as sensitive according to GDPR and additionally as confidential under Swedish Government Agency laws. Access to restricted data will require completion of a Data Access Request (DAR).  Each Data Access Request will be evaluated individually according to Swedish legislation. Describe the structure of the dataset: The dataset contains all raw genetic data for the human samples analyzed in the associated research article. The data is stored by datatype, in six folders. Each folder contains a metadata file and readme file. Amplicon_sequencing_fastqs (8Gb) Low_pass_WGS_Illumina (7Gb) Nanopore_direct_RNAseq (23.7 Gb) Nanopore_WGS (520 Gb) Sanger_sequencing (7 Mb) TRiXi_repeat_lengths (1 Mb) ABSTRACTPreferential usage of either X-chromosome, skewed X-inactivation (sXCI), can profoundly alter the penetrance and expressivity of X-linked traits in females, often with life-threatening consequences. Despite its clinical relevance, the true frequency, origins, and stability of sXCI in human tissues remain poorly understood, in part because many existing methods cannot determine XCI status in a substantial proportion of females, limiting their applicability in large-scale population studies. Here, we present TRiXi (Tandem Repeat-based Identification of X-Inactivation), a simple and highly sensitive technique capable of detecting sXCI from as little as 10 ng of archived human DNA. Applying TRiXi to over 1,000 neonatal cord blood samples from healthy infants, we demonstrate that pronounced sXCI at birth is common in humans. Use of longitudinal samples from the same donors revealed that sXCI patterns in skewed neonates were stably maintained into adolescence, whereas in non-skewed females, patterns fluctuated considerably over time. We further demonstrate that TRiXi accurately assesses skewing by comparison to orthogonal approaches, including allele-specific expression, allele-specific DNA methylation and the HUMARA assay. Using low-pass short-read sequencing, whole-genome long-read sequencing, and targeted exon sequencing, we exclude most known genetic drivers of sXCI in extremely skewed infants, suggesting contributions from stochastic processes or currently unknown genetic modifiers. Further, by inferring X-inactivation patterns in 4,571 adult tissues from 258 females in the GTEx cohort, we demonstrate that skewed XCI is not restricted to blood, revealing widespread sXCI across non-hematopoietic tissues in females. Our study represents the most comprehensive analysis of neonatal sXCI to date and reveals sXCI as a widespread and stable epigenetic trait. This can profoundly modify the penetrance of X-linked conditions with immediate implications for genetic diagnostics and our understanding of human disease variability. TRiXi provides a convenient and accessible approach to inform diagnosis of X-linked traits by assaying sXCI. Studying individuals with sXCI may yield critical insights into (i) the initiation of XCI and its underlying genomic elements, (ii) previously unrecognized lethal X-linked traits and (iii) improved polygenic risk prediction through incorporation of X-chromosome variation. LiU secure repository is a data repository that hosts research data which cannot be openly available for ethical or legal reasons. LiU secure repository is managed by Linköping University Library as a service to researchers at Linköping University (Sweden). For requests of access or further information, please contact datamanagement@liu.se