Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood
Abstract 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...
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2021
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oai:doaj.org-article:b671baf57f4d42619acfe5843fbbb3452021-11-14T12:44:42ZDeficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood10.1038/s41525-021-00256-y2056-7944https://doaj.org/article/b671baf57f4d42619acfe5843fbbb3452021-11-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00256-yhttps://doaj.org/toc/2056-7944Abstract 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.Michael A. LevyDavid B. BeckKay MetcalfeSofia DouzgouSivagamy SithambaramTrudie CottrellMuhammad AnsarJennifer KerkhofCyril MignotMarie-Christine NouguesBoris KerenHannah W. MooreRenske OegemaJacques C. GiltayMarleen SimonRichard H. van JaarsveldJessica BosMieke van HaelstM. Mahdi MotazackerElles M. J. BoonGijs W. E. SantenClaudia A. L. RuivenkampMarielle AldersTeresa Romeo LuperchioLeandros BoukasKeri RamseyVinodh NarayananG. Bradley SchaeferRoberto BonasioKimberly F. DohenyRoger E. StevensonSidharth BankaBekim SadikovicJill A. FahrnerNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-15 (2021) |
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DOAJ |
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DOAJ |
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Medicine R Genetics QH426-470 |
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Medicine R Genetics QH426-470 Michael A. Levy David B. Beck Kay Metcalfe Sofia Douzgou Sivagamy Sithambaram Trudie Cottrell Muhammad Ansar Jennifer Kerkhof Cyril Mignot Marie-Christine Nougues Boris Keren Hannah W. Moore Renske Oegema Jacques C. Giltay Marleen Simon Richard H. van Jaarsveld Jessica Bos Mieke van Haelst M. Mahdi Motazacker Elles M. J. Boon Gijs W. E. Santen Claudia A. L. Ruivenkamp Marielle Alders Teresa Romeo Luperchio Leandros Boukas Keri Ramsey Vinodh Narayanan G. Bradley Schaefer Roberto Bonasio Kimberly F. Doheny Roger E. Stevenson Sidharth Banka Bekim Sadikovic Jill A. Fahrner Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood |
| description |
Abstract 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 |
article |
| author |
Michael A. Levy David B. Beck Kay Metcalfe Sofia Douzgou Sivagamy Sithambaram Trudie Cottrell Muhammad Ansar Jennifer Kerkhof Cyril Mignot Marie-Christine Nougues Boris Keren Hannah W. Moore Renske Oegema Jacques C. Giltay Marleen Simon Richard H. van Jaarsveld Jessica Bos Mieke van Haelst M. Mahdi Motazacker Elles M. J. Boon Gijs W. E. Santen Claudia A. L. Ruivenkamp Marielle Alders Teresa Romeo Luperchio Leandros Boukas Keri Ramsey Vinodh Narayanan G. Bradley Schaefer Roberto Bonasio Kimberly F. Doheny Roger E. Stevenson Sidharth Banka Bekim Sadikovic Jill A. Fahrner |
| author_facet |
Michael A. Levy David B. Beck Kay Metcalfe Sofia Douzgou Sivagamy Sithambaram Trudie Cottrell Muhammad Ansar Jennifer Kerkhof Cyril Mignot Marie-Christine Nougues Boris Keren Hannah W. Moore Renske Oegema Jacques C. Giltay Marleen Simon Richard H. van Jaarsveld Jessica Bos Mieke van Haelst M. Mahdi Motazacker Elles M. J. Boon Gijs W. E. Santen Claudia A. L. Ruivenkamp Marielle Alders Teresa Romeo Luperchio Leandros Boukas Keri Ramsey Vinodh Narayanan G. Bradley Schaefer Roberto Bonasio Kimberly F. Doheny Roger E. Stevenson Sidharth Banka Bekim Sadikovic Jill A. Fahrner |
| author_sort |
Michael A. Levy |
| title |
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_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_sort |
deficiency of tet3 leads to a genome-wide dna hypermethylation episignature in human whole blood |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/b671baf57f4d42619acfe5843fbbb345 |
| work_keys_str_mv |
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