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Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood
TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other ch...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576018/ https://www.ncbi.nlm.nih.gov/pubmed/34750377 http://dx.doi.org/10.1038/s41525-021-00256-y |
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author | Levy, Michael A. Beck, David B. Metcalfe, Kay Douzgou, Sofia Sithambaram, Sivagamy Cottrell, Trudie Ansar, Muhammad Kerkhof, Jennifer Mignot, Cyril Nougues, Marie-Christine Keren, Boris Moore, Hannah W. Oegema, Renske Giltay, Jacques C. Simon, Marleen van Jaarsveld, Richard H. Bos, Jessica van Haelst, Mieke Motazacker, M. Mahdi Boon, Elles M. J. Santen, Gijs W. E. Ruivenkamp, Claudia A. L. Alders, Marielle Luperchio, Teresa Romeo Boukas, Leandros Ramsey, Keri Narayanan, Vinodh Schaefer, G. Bradley Bonasio, Roberto Doheny, Kimberly F. Stevenson, Roger E. Banka, Siddharth Sadikovic, Bekim Fahrner, Jill A. |
author_facet | Levy, Michael A. Beck, David B. Metcalfe, Kay Douzgou, Sofia Sithambaram, Sivagamy Cottrell, Trudie Ansar, Muhammad Kerkhof, Jennifer Mignot, Cyril Nougues, Marie-Christine Keren, Boris Moore, Hannah W. Oegema, Renske Giltay, Jacques C. Simon, Marleen van Jaarsveld, Richard H. Bos, Jessica van Haelst, Mieke Motazacker, M. Mahdi Boon, Elles M. J. Santen, Gijs W. E. Ruivenkamp, Claudia A. L. Alders, Marielle Luperchio, Teresa Romeo Boukas, Leandros Ramsey, Keri Narayanan, Vinodh Schaefer, G. Bradley Bonasio, Roberto Doheny, Kimberly F. Stevenson, Roger E. Banka, Siddharth Sadikovic, Bekim Fahrner, Jill A. |
author_sort | Levy, Michael A. |
collection | PubMed |
description | TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3’s direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease. |
format | Online Article Text |
id | pubmed-8576018 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85760182021-11-19 Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood Levy, Michael A. Beck, David B. Metcalfe, Kay Douzgou, Sofia Sithambaram, Sivagamy Cottrell, Trudie Ansar, Muhammad Kerkhof, Jennifer Mignot, Cyril Nougues, Marie-Christine Keren, Boris Moore, Hannah W. Oegema, Renske Giltay, Jacques C. Simon, Marleen van Jaarsveld, Richard H. Bos, Jessica van Haelst, Mieke Motazacker, M. Mahdi Boon, Elles M. J. Santen, Gijs W. E. Ruivenkamp, Claudia A. L. Alders, Marielle Luperchio, Teresa Romeo Boukas, Leandros Ramsey, Keri Narayanan, Vinodh Schaefer, G. Bradley Bonasio, Roberto Doheny, Kimberly F. Stevenson, Roger E. Banka, Siddharth Sadikovic, Bekim Fahrner, Jill A. NPJ Genom Med Article TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3’s direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease. Nature Publishing Group UK 2021-11-08 /pmc/articles/PMC8576018/ /pubmed/34750377 http://dx.doi.org/10.1038/s41525-021-00256-y Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access 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 http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Levy, Michael A. Beck, David B. Metcalfe, Kay Douzgou, Sofia Sithambaram, Sivagamy Cottrell, Trudie Ansar, Muhammad Kerkhof, Jennifer Mignot, Cyril Nougues, Marie-Christine Keren, Boris Moore, Hannah W. Oegema, Renske Giltay, Jacques C. Simon, Marleen van Jaarsveld, Richard H. Bos, Jessica van Haelst, Mieke Motazacker, M. Mahdi Boon, Elles M. J. Santen, Gijs W. E. Ruivenkamp, Claudia A. L. Alders, Marielle Luperchio, Teresa Romeo Boukas, Leandros Ramsey, Keri Narayanan, Vinodh Schaefer, G. Bradley Bonasio, Roberto Doheny, Kimberly F. Stevenson, Roger E. Banka, Siddharth Sadikovic, Bekim Fahrner, Jill A. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood |
title | Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood |
title_full | Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood |
title_fullStr | Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood |
title_full_unstemmed | Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood |
title_short | Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood |
title_sort | deficiency of tet3 leads to a genome-wide dna hypermethylation episignature in human whole blood |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576018/ https://www.ncbi.nlm.nih.gov/pubmed/34750377 http://dx.doi.org/10.1038/s41525-021-00256-y |
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