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

Publication date: Feb 06, 2020

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.

Beck, D.B., Petracovici, A., He, C., Moore, H.W., Louie, R.J., Ansar, M., Douzgou, S., Sithambaram, S., Cottrell, T., Santos-Cortez, R.L.P., Prijoles, E.J., Bend, R., Keren, B., Mignot, C., Nougues, M.C., ~Ounap, K., Reimand, T., Pajusalu, S., Zahid, M., Saqib, M.A.N., Buratti, J., Seaby, E.G., McWalter, K., Telegrafi, A., Baldridge, D., Shinawi, M., Leal, S.M., Schaefer, G.B., Stevenson, R.E., Banka, S., Bonasio, R., and Fahrner, J.A. Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency. 15198. 2020 Am J Hum Genet (106):2.

Concepts Keywords
Allelic Disorders epigenetic machinery
Assay Branches of biology
Autistic Genetics
Catalytic Epigenetics
Catalytic Domain DNA methylation
Catalyze 5-Hydroxymethylcytosine
Chromatin Genetic disorder
Coding Region DNA demethylation
Cytosine
Demethylation
Embryogenesis
Epigenetic
Epigenetic Inheritance
Frameshift
Germline
Haploinsufficiency
Histone
Hypotonia
Intellectual Disability
Mendelian
Mendelian Disorders
Methylation
Methylcytosine
Missense
Mono
Movement Disorders
Pathogenic
Pediatric
Phenotypic
Zygote

Semantics

Type Source Name
pathway REACTOME DNA methylation
disease MESH haploinsufficiency
disease MESH intellectual disability
disease MESH hypotonia
disease MESH movement disorders
disease MESH growth
disease MESH abnormalities

Original Article

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