TY - JOUR
T1 - Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery
T2 - TET3 Deficiency
AU - Beck, David B.
AU - Petracovici, Ana
AU - He, Chongsheng
AU - Moore, Hannah W.
AU - Louie, Raymond J.
AU - Ansar, Muhammad
AU - Douzgou, Sofia
AU - Sithambaram, Sivagamy
AU - Cottrell, Trudie
AU - Santos-Cortez, Regie Lyn P.
AU - Prijoles, Eloise J.
AU - Bend, Renee
AU - Keren, Boris
AU - Mignot, Cyril
AU - Nougues, Marie Christine
AU - Õunap, Katrin
AU - Reimand, Tiia
AU - Pajusalu, Sander
AU - Zahid, Muhammad
AU - Saqib, Muhammad Arif Nadeem
AU - Buratti, Julien
AU - Seaby, Eleanor G.
AU - McWalter, Kirsty
AU - Telegrafi, Aida
AU - Baldridge, Dustin
AU - Shinawi, Marwan
AU - Leal, Suzanne M.
AU - Schaefer, G. Bradley
AU - Stevenson, Roger E.
AU - Banka, Siddharth
AU - Bonasio, Roberto
AU - Fahrner, Jill A.
N1 - Publisher Copyright:
© 2019 American Society of Human Genetics
PY - 2020/2/6
Y1 - 2020/2/6
N2 - 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.
AB - 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.
KW - 5-hydroxymethylcytosine
KW - 5-methylcytosine
KW - DNA methylation
KW - TET
KW - epigenetic
KW - genetic
KW - intellectual disability
UR - http://www.scopus.com/inward/record.url?scp=85078736549&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2019.12.007
DO - 10.1016/j.ajhg.2019.12.007
M3 - Article
C2 - 31928709
AN - SCOPUS:85078736549
SN - 0002-9297
VL - 106
SP - 234
EP - 245
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -