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

Autor: Trudie Cottrell, Jacques C. Giltay, Richard H. van Jaarsveld, Elles M. J. Boon, Roger E. Stevenson, Michael A. Levy, Kimberly F. Doheny, Bekim Sadikovic, G. Bradley Schaefer, Roberto Bonasio, Muhammad Ansar, Vinodh Narayanan, Mieke M. van Haelst, Jill A. Fahrner, Marleen Simon, David B. Beck, Claudia A. L. Ruivenkamp, Sivagamy Sithambaram, Teresa Romeo Luperchio, Leandros Boukas, Marie-Christine Nougues, Hannah W. Moore, Marielle Alders, Renske Oegema, M. Mahdi Motazacker, Kay Metcalfe, Cyril Mignot, Jennifer Kerkhof, Gijs W. E. Santen, Jessica Bos, Sofia Douzgou, Siddharth Banka, Keri Ramsey, Boris Keren
Přispěvatelé: Human Genetics, ACS - Pulmonary hypertension & thrombosis, ANS - Complex Trait Genetics, AR&D - Amsterdam Reproduction & Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: npj Genomic Medicine, 6(1):92. Nature Publishing Group
NPJ Genomic Medicine
npj Genomic Medicine, 6(1). NATURE PORTFOLIO
Levy, M A, Beck, D B, Metcalfe, K, Douzgou, S, Sithambaram, S, Cottrell, T, Ansar, M, Kerkhof, J, Mignot, C, Nougues, M-C, Keren, B, Moore, H W, Oegema, R, Giltay, J C, Simon, M, van Jaarsveld, R H, Bos, J, van Haelst, M, Motazacker, M M, Boon, E M J, Santen, G W E, Ruivenkamp, C A L, Alders, M, Luperchio, T R, Boukas, L, Ramsey, K, Narayanan, V, Schaefer, G B, Bonasio, R, Doheny, K F, Stevenson, R E, Banka, S, Sadikovic, B & Fahrner, J A 2021, ' Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood ', NPJ GENOMIC MEDICINE, vol. 6, no. 1, 92 . https://doi.org/10.1038/s41525-021-00256-y
NPJ GENOMIC MEDICINE, 6(1):92. Nature Publishing Group
npj Genomic Medicine, Vol 6, Iss 1, Pp 1-15 (2021)
ISSN: 2056-7944
DOI: 10.1038/s41525-021-00256-y
Popis: 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.
Databáze: OpenAIRE
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