Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome

Sunwoo Lee; Eguzkine Ochoa; Magdalena Badura-Stronka; Deirdre Donnelly; Damien Lederer; Sally A. Lynch; Alice Gardham; Jenny Morton; Helen Stewart; France Docquier; Fay Rodger; Ezequiel Martin; Ana Toribio; Eamonn R. Maher; Meena Balasubramanian

doi:10.1038/s41431-023-01422-9

Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome

Sunwoo Lee, Eguzkine Ochoa, Magdalena Badura-Stronka, Deirdre Donnelly, Damien Lederer, Sally A. Lynch, Alice Gardham, Jenny Morton, Helen Stewart, France Docquier, Fay Rodger, Ezequiel Martin, Ana Toribio, Eamonn R. Maher, Meena Balasubramanian

Aston Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.

Original language	English
Pages (from-to)	1040-1047
Number of pages	8
Journal	European Journal of Human Genetics
Volume	31
Issue number	9
Early online date	5 Jul 2023
DOIs	https://doi.org/10.1038/s41431-023-01422-9
Publication status	Published - Sept 2023

Bibliographical note

Copyright © The Author(s), 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

Keywords

Humans
DNA Methylation
Epigenome
Germ Cells
Germ-Line Mutation
Neurodevelopmental Disorders/genetics

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10.1038/s41431-023-01422-9

Sunwoo Lee et al_Germline pathogenic variants in HNRNPU and blood methylome
Copyright © The Author(s), 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
Final published version, 1.57 MBLicence: CC BY 4.0

Cite this

Lee, S., Ochoa, E., Badura-Stronka, M., Donnelly, D., Lederer, D., Lynch, S. A., Gardham, A., Morton, J., Stewart, H., Docquier, F., Rodger, F., Martin, E., Toribio, A., Maher, E. R., & Balasubramanian, M. (2023). Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome. European Journal of Human Genetics, 31(9), 1040-1047. https://doi.org/10.1038/s41431-023-01422-9

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abstract = "HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.",

keywords = "Humans, DNA Methylation, Epigenome, Germ Cells, Germ-Line Mutation, Neurodevelopmental Disorders/genetics",

author = "Sunwoo Lee and Eguzkine Ochoa and Magdalena Badura-Stronka and Deirdre Donnelly and Damien Lederer and Lynch, {Sally A.} and Alice Gardham and Jenny Morton and Helen Stewart and France Docquier and Fay Rodger and Ezequiel Martin and Ana Toribio and Maher, {Eamonn R.} and Meena Balasubramanian",

note = "Copyright {\textcopyright} The Author(s), 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.",

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Lee, S, Ochoa, E, Badura-Stronka, M, Donnelly, D, Lederer, D, Lynch, SA, Gardham, A, Morton, J, Stewart, H, Docquier, F, Rodger, F, Martin, E, Toribio, A, Maher, ER & Balasubramanian, M 2023, 'Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome', European Journal of Human Genetics, vol. 31, no. 9, pp. 1040-1047. https://doi.org/10.1038/s41431-023-01422-9

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T1 - Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome

AU - Lee, Sunwoo

AU - Ochoa, Eguzkine

AU - Badura-Stronka, Magdalena

AU - Donnelly, Deirdre

AU - Lederer, Damien

AU - Lynch, Sally A.

AU - Gardham, Alice

AU - Morton, Jenny

AU - Stewart, Helen

AU - Docquier, France

AU - Rodger, Fay

AU - Martin, Ezequiel

AU - Toribio, Ana

AU - Maher, Eamonn R.

AU - Balasubramanian, Meena

N1 - Copyright © The Author(s), 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

PY - 2023/9

Y1 - 2023/9

N2 - HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.

AB - HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.

KW - Humans

KW - DNA Methylation

KW - Epigenome

KW - Germ Cells

KW - Germ-Line Mutation

KW - Neurodevelopmental Disorders/genetics

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DO - 10.1038/s41431-023-01422-9

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JO - European Journal of Human Genetics

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ER -

Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome

Abstract

Bibliographical note

Keywords

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