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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 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.

SUBMITTER: Levy MA

PROVIDER: S-EPMC8576018 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Levy Michael A MA Beck David B DB Metcalfe Kay K Douzgou Sofia S Sithambaram Sivagamy S Cottrell Trudie T Ansar Muhammad M Kerkhof Jennifer J Mignot Cyril C Nougues Marie-Christine MC Keren Boris B Moore Hannah W HW Oegema Renske R Giltay Jacques C JC Simon Marleen M van Jaarsveld Richard H RH Bos Jessica J van Haelst Mieke M Motazacker M Mahdi MM Boon Elles M J EMJ Santen Gijs W E GWE Ruivenkamp Claudia A L CAL Alders Marielle M Luperchio Teresa Romeo TR Boukas Leandros L Ramsey Keri K Narayanan Vinodh V Schaefer G Bradley GB Bonasio Roberto R Doheny Kimberly F KF Stevenson Roger E RE Banka Siddharth S Sadikovic Bekim B Fahrner Jill A JA

NPJ genomic medicine 20211108 1

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 sy ...[more]

PMID: 34750377

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Dataset Information

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

Publications

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

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