Single-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in Cerebral Cavernous Malformations
© 2023. The Author(s)..
Cerebral Cavernous Malformations (CCMs) are vascular malformations of the central nervous system which can lead to moderate to severe neurological phenotypes in patients. A majority of CCM lesions are driven by a cancer-like three-hit mutational mechanism, including a somatic, activating mutation in the oncogene PIK3CA, as well as biallelic loss-of-function mutations in a CCM gene. However, standard sequencing approaches often fail to yield a full complement of pathogenic mutations in many CCMs. We suggest this reality reflects the limited sensitivity to identify low-frequency variants and the presence of mutations undetectable with bulk short-read sequencing. Here we report a single-nucleus DNA-sequencing approach that leverages the underlying biology of CCMs to identify lesions with somatic loss-of-heterozygosity, a class of such hidden mutations. We identify an alternative genetic mechanism for CCM pathogenesis and establish a method that can be repurposed to investigate the genetic underpinning of other disorders with multiple somatic mutations.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 02. Nov., Seite 7009 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ressler, Andrew K [VerfasserIn] |
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| Links: |
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| Themen: |
Apoptosis Regulatory Proteins |
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| Anmerkungen: |
Date Completed 06.11.2023 Date Revised 22.12.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-42908-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364111909 |
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| 245 | 1 | 0 | |a Single-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in Cerebral Cavernous Malformations |
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| 520 | |a © 2023. The Author(s). | ||
| 520 | |a Cerebral Cavernous Malformations (CCMs) are vascular malformations of the central nervous system which can lead to moderate to severe neurological phenotypes in patients. A majority of CCM lesions are driven by a cancer-like three-hit mutational mechanism, including a somatic, activating mutation in the oncogene PIK3CA, as well as biallelic loss-of-function mutations in a CCM gene. However, standard sequencing approaches often fail to yield a full complement of pathogenic mutations in many CCMs. We suggest this reality reflects the limited sensitivity to identify low-frequency variants and the presence of mutations undetectable with bulk short-read sequencing. Here we report a single-nucleus DNA-sequencing approach that leverages the underlying biology of CCMs to identify lesions with somatic loss-of-heterozygosity, a class of such hidden mutations. We identify an alternative genetic mechanism for CCM pathogenesis and establish a method that can be repurposed to investigate the genetic underpinning of other disorders with multiple somatic mutations | ||
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| 700 | 1 | |a Gallione, Carol J |e verfasserin |4 aut | |
| 700 | 1 | |a Lightle, Rhonda |e verfasserin |4 aut | |
| 700 | 1 | |a Allen, Andrew S |e verfasserin |4 aut | |
| 700 | 1 | |a Awad, Issam A |e verfasserin |4 aut | |
| 700 | 1 | |a Marchuk, Douglas A |e verfasserin |4 aut | |
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