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

David B Beck; Ana Petracovici; Chongsheng He; Hannah W Moore; Raymond J Louie; Muhammad Ansar; Sofia Douzgou; Sivagamy Sithambaram; Trudie Cottrell; Regie Lyn P Santos-Cortez; Eloise J Prijoles; Renee Bend; Boris Keren; Cyril Mignot; Marie-Christine Nougues; Katrin Õunap; Tiia Reimand; Sander Pajusalu; Muhammad Zahid; Muhammad Arif Nadeem Saqib; Julien Buratti; Eleanor G Seaby; Kirsty McWalter; Aida Telegrafi; Dustin Baldridge; Marwan Shinawi; Suzanne M Leal; G Bradley Schaefer; Roger E Stevenson; Siddharth Banka; Roberto Bonasio; Jill A Fahrner

doi:10.1016/j.ajhg.2019.12.007

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

Am J Hum Genet. 2020 Feb 6;106(2):234-245. doi: 10.1016/j.ajhg.2019.12.007. Epub 2020 Jan 9.

Authors

David B Beck¹, Ana Petracovici², Chongsheng He³, Hannah W Moore⁴, Raymond J Louie⁴, Muhammad Ansar⁵, Sofia Douzgou⁶, Sivagamy Sithambaram⁷, Trudie Cottrell⁷, Regie Lyn P Santos-Cortez⁸, Eloise J Prijoles⁴, Renee Bend⁴, Boris Keren⁹, Cyril Mignot¹⁰, Marie-Christine Nougues¹¹, Katrin Õunap¹², Tiia Reimand¹³, Sander Pajusalu¹⁴, Muhammad Zahid⁵, Muhammad Arif Nadeem Saqib¹⁵, Julien Buratti⁹, Eleanor G Seaby¹⁶, Kirsty McWalter¹⁷, Aida Telegrafi¹⁷, Dustin Baldridge¹⁸, Marwan Shinawi¹⁸, Suzanne M Leal¹⁹, G Bradley Schaefer²⁰, Roger E Stevenson⁴, Siddharth Banka⁶, Roberto Bonasio²¹, Jill A Fahrner²²

Affiliations

¹ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
² Graduate Group in Genetics and Epigenetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
³ Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Current address: Hunan Key Laboratory of Plant Functional Genomics and Developmental Regulation, Hunan University, Changsha 410082 Hunan, P.R. China.
⁴ Greenwood Genetic Center, Greenwood, SC 29646, USA.
⁵ Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, 45320 Islamabad, Pakistan.
⁶ Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.
⁷ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.
⁸ Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
⁹ Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, Paris 75013, France.
¹⁰ Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, Paris 75013, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris 75013, France.
¹¹ Assistance Publique-Hôpitaux de Paris, Armand Trousseau Hospital, Department of Neuropediatrics, Paris 75012, France.
¹² Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu 50406, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia.
¹³ Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu 50406, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia; Chair of Human Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50406, Estonia.
¹⁴ Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu 50406, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia; Yale University School of Medicine, Department of Genetics, New Haven, CT 06510, USA.
¹⁵ Pakistan Health Research Council, 45320 Islamabad, Pakistan.
¹⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁷ GeneDx, Gaithersburg, MD 20877, USA.
¹⁸ Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁹ Center for Statistical Genetics, Gertrude H. Sergievsky Center, Taub Institute for Alzheimer's D disease and the Aging Brain, Department of Neurology, Columbia University Medical Center, 630 W 168th St, New York, NY 10032, USA.
²⁰ University of Arkansas for Medical Sciences, Lowell, AK 72745, USA.
²¹ Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
²² Department of Pediatrics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: [email protected].

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.

Keywords: 5-hydroxymethylcytosine; 5-methylcytosine; DNA methylation; TET; epigenetic; genetic; intellectual disability.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Amino Acid Sequence
Autistic Disorder / genetics
Autistic Disorder / pathology
Child
Child, Preschool
DNA Demethylation*
Developmental Disabilities / genetics*
Developmental Disabilities / pathology*
Dioxygenases / chemistry
Dioxygenases / deficiency*
Dioxygenases / genetics
Embryonic Development
Female
Gene Expression Regulation, Developmental
Growth Disorders / genetics
Growth Disorders / pathology
Humans
Infant
Male
Middle Aged
Movement Disorders / genetics
Movement Disorders / pathology
Pedigree
Protein Conformation
Sequence Homology
Young Adult

Substances

TET3 protein, human
Dioxygenases

Abstract

Publication types

MeSH terms

Substances

Grants and funding