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 of NR0B1 (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 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.ConclusionHere 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.

A Novel Look at Dosage-Sensitive Sex Locus Xp21.2 in a Case of 46,XY Partial Gonadal Dysgenesis without NR0B1 Duplication

“…A patient with complete XY GD with two duplications and two small deletions that did not include NR0B1 was recently described [21]. High-throughput chromosome conformation capture (Hi-C) analysis of this case revealed rearrangement of a topologicalassociated domain (TAD) boundary close to NR0B1 which was associated with neo-TAD formation that may cause enhancer hijacking and ectopic NR0B1 expression.…”

Anomalies in Human Sex Determination: Usefulness of a Combined Cytogenetic Approach to Characterize an Additional Case with Xp Functional Disomy Associated with 46,XY Gonadal Dysgenesis

“…This justifies its relative contribution to the identification of CNV related to different DSD phenotypes by characterizing the exact size, and breakpoints as well as the expansion of the pool of candidate genes in disease pathogenesis in a single step. The discovery of new genomic analysis tools such as Hi-C technology may provide new insights into the physical genomic interactions and support the hypothesis that a common genomic region can be bound by both pro-testis and pro-ovarian transcription factors and genes ( 35 , 36 ).…”

Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development

“…Thus, the deletion may have altered NR0B1 expression. Recently, duplications containing a potential enhancer element have been identified in two individuals with 46,XY DSD [ 96 , 97 ]. This enhancer element resides in a topologically associating domain (TAD) that contains TASL and GK in the male control genome, but not NR0B1 [ 96 ].…”

“…Recently, duplications containing a potential enhancer element have been identified in two individuals with 46,XY DSD [ 96 , 97 ]. This enhancer element resides in a topologically associating domain (TAD) that contains TASL and GK in the male control genome, but not NR0B1 [ 96 ]. In contrast, genomic rearrangements in one of the two patients disrupted conventional TAD, creating an aberrant interaction between NR0B1 and the enhancer element [ 96 ].…”

“…This enhancer element resides in a topologically associating domain (TAD) that contains TASL and GK in the male control genome, but not NR0B1 [ 96 ]. In contrast, genomic rearrangements in one of the two patients disrupted conventional TAD, creating an aberrant interaction between NR0B1 and the enhancer element [ 96 ]. Although whether the duplication in another patient affects the TAD around NR0B1 remains to be investigated [ 97 ], the duplication might have altered the spatial relationship between NR0B1 and this putative enhancer or other regulatory elements, upregulating the transcription of NR0B1 .…”