Disruption of the topologically associated domain at Xp21.2 is related to 46,XY gonadal dysgenesis

<jats:sec><jats:title>Background</jats:title><jats:p>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<jats:italic>NR0B1</jats:italic>(<jats:italic>DAX1</jats:italic>), but the exact disease mechanism remains unknown.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified two unrelated patients: one showing a complex rearrangement upstream of<jats:italic>NR0B1</jats:italic>and a second harbouring a 1.2 Mb triplication, including<jats:italic>NR0B1</jats:italic>. Whole genome sequencing and Hi-C analysis revealed the rewiring of a topological-associated domain (TAD) boundary close to<jats:italic>NR0B1</jats:italic>associated with neo-TAD formation and may cause enhancer hijacking and ectopic<jats:italic>NR0B1</jats:italic>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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Here we present a general mechanism how deletions, duplications or inversions at the<jats:italic>NR0B1</jats:italic>locus can lead to partial or complete GD by disrupting the cognate TAD in the vicinity of<jats:italic>NR0B1</jats:italic>. 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.</jats:p></jats:sec>