Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency - Sorbonne Université Access content directly
Journal Articles American Journal of Human Genetics Year : 2020

Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency

Ana Petracovici
  • Function : Author
Chongsheng He
  • Function : Author
Hannah Moore
  • Function : Author
Sivagamy Sithambaram
  • Function : Author
Trudie Cottrell
  • Function : Author
Regie Lyn P. Santos-Cortez
  • Function : Author
Eloise Prijoles
  • Function : Author
Renee Bend
  • Function : Author
Tiia Reimand
  • Function : Author
Muhammad Arif Nadeem Saqib
  • Function : Author
Julien Buratti
  • Function : Author
Eleanor Seaby
  • Function : Author
Kirsty Mcwalter
  • Function : Author
Aida Telegrafi
  • Function : Author
Dustin Baldridge
  • Function : Author
Marwan Shinawi
  • Function : Author
Suzanne Leal
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G. Bradley Schaefer
  • Function : Author
Roger Stevenson
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Siddharth Banka
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Roberto Bonasio
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Jill Fahrner
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Abstract

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.

Dates and versions

hal-04573567 , version 1 (13-05-2024)

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David Beck, Ana Petracovici, Chongsheng He, Hannah Moore, Raymond Louie, et al.. Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency. American Journal of Human Genetics, 2020, 106 (2), pp.234-245. ⟨10.1016/j.ajhg.2019.12.007⟩. ⟨hal-04573567⟩
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