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Two families with TET3-related disorder showing neurodevelopmental delay with craniofacial dysmorphisms

Journal of Human Genetics volume 67, pages 157–164 (2022)Cite this article

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Abstract

TET3 at 2p13.1 encodes tet methylcytosine dioxygenase 3, a demethylation enzyme that converts 5-methylcytosine to 5-hydroxymethylcytosine. Beck et al. reported that patients with TET3 abnormalities in either an autosomal dominant or recessive inheritance fashion clinically showed global developmental delay, intellectual disability, and dysmorphisms. In this study, exome sequencing identified both mono- and biallelic TET3 variants in two families: a de novo variant NM_001287491.1:c.3028 A > G:p.(Asn1010Asp), and compound heterozygous variants NM_001287491.1:c.[2077 C > T];[2896 T > G],p.[Gln693*];[Cys966Gly]. Despite the different inheritance modes, the affected individuals showed similar phenotypic features. Including these three patients, only 14 affected individuals have been reported to date. The accumulation of data regarding individuals with TET3-related disorder is necessary to describe their clinical spectrum.

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Fig. 1: Clinical features of three patients with TET3-related disorder.
Fig. 2: Pathogenic variants causing TET3-related disorder.
Fig. 3: Crystal structure of TET2 (PDB:5DEU) [19] bound to DNA.

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Acknowledgements

We thank all patients and their families for their participation in this study. We would like to thank N. Watanabe, T. Miyama, M. Sato, S. Sugimoto, and K. Takabe for their technical assistance. We thank Catherine Perfect, MA (Cantab), from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript. R. Seyama, N. Tsuchida, Y. Uchiyama and N. Matsumoto contributed to the study design. R. Seyama, N. Tsuchida, K. Hamada, K. Ogata, Y. Uchiyama and N. Matsumoto performed the data analysis. Y. Okada, S. Sakata, S. Okada and N. Okamoto evaluated clinical information of patients. R. Seyama, Y. Uchiyama and N. Matsumoto prepared the manuscript. N. Matsumoto finalized the manuscript. All authors critically read the manuscript, corrected, and approved the final version of the manuscript.

Funding

This study was supported by the Japan Agency for Medical Research and Development (AMED) (grant numbers: JP21ek0109486, JP21ek0109549, JP21cm0106503, and JP21ek0109493); JSPS KAKENHI (grant numbers: JP20K07907, JP20K08164, JP21k15097, JP20K17428, JP21K07869, and JP20K16932); the Takeda Science Foundation; and the Ichiro Kanehara Foundation for the Promotion of Medical Science and Medical Care.

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Authors and Affiliations

  1. Department of Human Genetics, Yokohama City University, Yokohama, Japan

    Rie Seyama, Naomi Tsuchida, Yoshiteru Azuma, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Satoko Miyatake, Takeshi Mizuguchi, Yuri Uchiyama & Naomichi Matsumoto

  2. Department of Obstetrics and Gynecology, Juntendo University, Tokyo, Japan

    Rie Seyama & Atsuo Itakura

  3. Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan

    Naomi Tsuchida & Yuri Uchiyama

  4. Department of Pediatrics, National Hospital Organization Higashihiroshima Medical Center, Higashihiroshima, Japan

    Yasuyuki Okada

  5. Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan

    Sonoko Sakata & Satoshi Okada

  6. Department of Biochemistry, Yokohama City University, Yokohama, Japan

    Keisuke Hamada & Kazuhiro Ogata

  7. Department of Pediatrics, Aichi Medical University, Nagakute, Japan

    Yoshiteru Azuma

  8. Department of Obstetrics and Gynecology, Juntendo University Urayasu Hospital, Chiba, Japan

    Shintaro Makino

  9. Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Osaka, Japan

    Nobuhiko Okamoto

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  1. Rie Seyama
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Correspondence to Naomichi Matsumoto.

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Seyama, R., Tsuchida, N., Okada, Y. et al. Two families with TET3-related disorder showing neurodevelopmental delay with craniofacial dysmorphisms. J Hum Genet 67, 157–164 (2022). https://doi.org/10.1038/s10038-021-00986-y

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