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

Abstract

BackgroundDuplications at the Xp21.2 locus have previously been linked to 46,XY gonadal dysgenesis (GD), which is thought to result from gene dosage effects ofNR0B1(DAX1), but the exact disease mechanism remains unknown.MethodsPatients 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).ResultsWe identified two unrelated patients: one showing a complex rearrangement upstream ofNR0B1and a second harbouring a 1.2 Mb triplication, includingNR0B1. Whole genome sequencing and Hi-C analysis revealed the rewiring of a topological-associated domain (TAD) boundary close toNR0B1associated with neo-TAD formation and may cause enhancer hijacking and ectopicNR0B1expression. 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.ConclusionHere we present a general mechanism how deletions, duplications or inversions at theNR0B1locus can lead to partial or complete GD by disrupting the cognate TAD in the vicinity ofNR0B1. 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.