Disruption of the topologically associated domain at Xp21.2 is related to 46,XY gonadal dysgenesis
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:60 |
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| Enthalten in: |
Journal of medical genetics - 60(2023), 5 vom: 13. Mai, Seite 469-476 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Meinel, Jakob A [VerfasserIn] |
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| Links: |
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| Themen: |
Gene expression regulation |
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| Anmerkungen: |
Date Completed 24.04.2023 Date Revised 23.06.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1136/jmg-2022-108635 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM347428118 |
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| 100 | 1 | |a Meinel, Jakob A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Disruption of the topologically associated domain at Xp21.2 is related to 46,XY gonadal dysgenesis |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a gene expression regulation | |
| 650 | 4 | |a gene rearrangement | |
| 650 | 4 | |a high-throughput nucleotide sequencing | |
| 650 | 4 | |a sequence analysis, DNA | |
| 650 | 4 | |a sex determination processes | |
| 700 | 1 | |a Yumiceba, Verónica |e verfasserin |4 aut | |
| 700 | 1 | |a Künstner, Axel |e verfasserin |4 aut | |
| 700 | 1 | |a Schultz, Kristin |e verfasserin |4 aut | |
| 700 | 1 | |a Kruse, Nathalie |e verfasserin |4 aut | |
| 700 | 1 | |a Kaiser, Frank J |e verfasserin |4 aut | |
| 700 | 1 | |a Holterhus, Paul-Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Claviez, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Hiort, Olaf |e verfasserin |4 aut | |
| 700 | 1 | |a Busch, Hauke |e verfasserin |4 aut | |
| 700 | 1 | |a Spielmann, Malte |e verfasserin |4 aut | |
| 700 | 1 | |a Werner, Ralf |e verfasserin |4 aut | |
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