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

TitleDelineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency.
Publication TypeJournal Article
Year of Publication2020
AuthorsBeck, DB, Petracovici, A, He, C, Moore, HW, Louie, RJ, Ansar, M, Douzgou, S, Sithambaram, S, Cottrell, T, Santos-Cortez, RLyn P, Prijoles, EJ, Bend, R, Keren, B, Mignot, C, Nougues, M-C, Õunap, K, Reimand, T, Pajusalu, S, Zahid, M, Saqib, MArif Nadee, Buratti, J, Seaby, EG, McWalter, K, Telegrafi, A, Baldridge, D, Shinawi, M, Leal, SM, G Schaefer, B, Stevenson, RE, Banka, S, Bonasio, R, Fahrner, JA
JournalAm J Hum Genet
Date Published2020 02 06
KeywordsAdult, Amino Acid Sequence, Autistic Disorder, Child, Child, Preschool, Developmental Disabilities, Dioxygenases, DNA Demethylation, Embryonic Development, Female, Gene Expression Regulation, Developmental, Growth Disorders, Humans, Infant, Male, Middle Aged, Movement Disorders, Pedigree, Protein Conformation, Sequence Homology, Young Adult

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.

Alternate JournalAm J Hum Genet
PubMed ID31928709
PubMed Central IDPMC7010978
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 GM127408 / GM / NIGMS NIH HHS / United States
DP2 MH107055 / MH / NIMH NIH HHS / United States
P50 HD103538 / HD / NICHD NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
T32 HD083185 / HD / NICHD NIH HHS / United States
K08 HD086250 / HD / NICHD NIH HHS / United States
/ WT / Wellcome Trust / United Kingdom