Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood - Sorbonne Université Access content directly
Journal Articles npj Genomic Medicine Year : 2021

Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood

Michael A Levy
  • Function : Author
David B Beck
Kay Metcalfe
  • Function : Author
Sofia Douzgou
Sivagamy Sithambaram
  • Function : Author
Trudie Cottrell
  • Function : Author
Muhammad Ansar
  • Function : Author
Jennifer Kerkhof
Marie-Christine Nougues
  • Function : Author
Boris Keren
  • Function : Author
Hannah W Moore
  • Function : Author
Renske Oegema
Jacques C Giltay
  • Function : Author
Marleen Simon
  • Function : Author
Richard H van Jaarsveld
Jessica Bos
  • Function : Author
Mieke van Haelst
  • Function : Author
M Mahdi Motazacker
  • Function : Author
Elles M J Boon
  • Function : Author
Gijs W E Santen
  • Function : Author
Claudia a L Ruivenkamp
  • Function : Author
Marielle Alders
  • Function : Author
Teresa Romeo Luperchio
  • Function : Author
Leandros Boukas
  • Function : Author
Keri Ramsey
  • Function : Author
Vinodh Narayanan
G Bradley Schaefer
  • Function : Author
Roberto Bonasio
Kimberly F Doheny
  • Function : Author
Roger E Stevenson
Siddharth Banka
  • Function : Author
Bekim Sadikovic
  • Function : Author
  • PersonId : 1103091
Jill A Fahrner
M. Mahdi Motazacker
  • Function : Author
G. Bradley Schaefer
  • Function : Author

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.
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hal-04534039 , version 1 (05-04-2024)

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Michael A Levy, David B Beck, Kay Metcalfe, Sofia Douzgou, Sivagamy Sithambaram, et al.. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood. npj Genomic Medicine, 2021, 6 (1), pp.92. ⟨10.1038/s41525-021-00256-y⟩. ⟨hal-04534039⟩
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