PT - JOURNAL ARTICLE AU - Jakob A Meinel AU - Verónica Yumiceba AU - Axel Künstner AU - Kristin Schultz AU - Nathalie Kruse AU - Frank J Kaiser AU - Paul-Martin Holterhus AU - Alexander Claviez AU - Olaf Hiort AU - Hauke Busch AU - Malte Spielmann AU - Ralf Werner TI - Disruption of the topologically associated domain at Xp21.2 is related to 46,XY gonadal dysgenesis AID - 10.1136/jmg-2022-108635 DP - 2022 Sep 09 TA - Journal of Medical Genetics PG - jmedgenet-2022-108635 4099 - http://jmg.bmj.com/content/early/2022/09/19/jmg-2022-108635.short 4100 - http://jmg.bmj.com/content/early/2022/09/19/jmg-2022-108635.full AB - Background Duplications at the Xp21.2 locus have previously been linked to 46,XY gonadal dysgenesis (GD), which is thought to result from gene dosage effects of NR0B1 (DAX1), but the exact disease mechanism remains unknown.Methods Patients with 46,XY GD were analysed by whole genome sequencing. Identified structural variants were confirmed by array CGH and analysed by high-throughput chromosome conformation capture (Hi-C).Results We identified two unrelated patients: one showing a complex rearrangement upstream of NR0B1 and a second harbouring a 1.2 Mb triplication, including NR0B1. Whole genome sequencing and Hi-C analysis revealed the rewiring of a topological-associated domain (TAD) boundary close to NR0B1 associated with neo-TAD formation and may cause enhancer hijacking and ectopic NR0B1 expression. Modelling of previous Xp21.2 structural variations associated with isolated GD support our hypothesis and predict similar neo-TAD formation as well as TAD fusion.Conclusion Here we present a general mechanism how deletions, duplications or inversions at the NR0B1 locus can lead to partial or complete GD by disrupting the cognate TAD in the vicinity of NR0B1. This model not only allows better diagnosis of GD with copy number variations (CNVs) at Xp21.2, but also gives deeper insight on how spatiotemporal activation of developmental genes can be disrupted by reorganised TADs causing impairment of gonadal development.All data relevant to the study are included in the article or uploaded as supplementary information.