Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders

Hui Guo, Elisa Bettella, Paul C. Marcogliese, Rongjuan Zhao, Jonathan C. Andrews, Tomasz J. Nowakowski, Madelyn A. Gillentine, Kendra Hoekzema, Tianyun Wang, Huidan Wu, Sharayu Jangam, Cenying Liu, Hailun Ni, Marjolein H. Willemsen, Bregje W. Bon, Tuula Rinne, Servi J. C. Stevens, Tjitske Kleefstra, Han G. Brunner, Helger G. Yntema, Min Long, Wenjing Zhao, Zhengmao Hu, Cindy Colson, Nicolas Richard, Charles E. Schwartz, Corrado Romano, Lucia Castiglia, Maria Bottitta, Shweta U. Dhar, Deanna J. Erwin, Lisa Emrick, Boris Keren, Alexandra Afenjar, Baosheng Zhu, Bing Bai, Pawel Stankiewicz, Kristin Herman, Saadet Mercimek-Andrews, Jane Juusola, Amy B. Wilfert, Rami Abou Jamra, Benjamin Büttner, Heather C. Mefford, Alison M. Muir, Ingrid E. Scheffer, Brigid M. Regan, Stephen Malone, Jozef Gecz, Jan Cobben, Marjan M. Weiss, Quinten Waisfisz, Emilia K. Bijlsma, Mariëtte J. V. Hoffer, Claudia A. L. Ruivenkamp, Stefano Sartori, Fan Xia, Jill A. Rosenfeld, Raphael A. Bernier, Michael F. Wangler, Shinya Yamamoto, Kun Xia, Alexander P. A. Stegmann, Hugo J. Bellen, Alessandra Murgia () and Evan E. Eichler ()
Additional contact information
Hui Guo: University of Washington School of Medicine
Elisa Bettella: University of Padua
Paul C. Marcogliese: Baylor College of Medicine
Rongjuan Zhao: Central South University
Jonathan C. Andrews: Baylor College of Medicine
Tomasz J. Nowakowski: University of California, San Francisco
Madelyn A. Gillentine: University of Washington School of Medicine
Kendra Hoekzema: University of Washington School of Medicine
Tianyun Wang: University of Washington School of Medicine
Huidan Wu: Central South University
Sharayu Jangam: Baylor College of Medicine
Cenying Liu: Central South University
Hailun Ni: Central South University
Marjolein H. Willemsen: Radboud University Medical Center
Bregje W. Bon: Radboud University Medical Center
Tuula Rinne: Radboud University Medical Center
Servi J. C. Stevens: Maastricht University Medical Center
Tjitske Kleefstra: Radboud University Medical Center
Han G. Brunner: Radboud University Medical Center
Helger G. Yntema: Radboud University Medical Center
Min Long: Central South University
Wenjing Zhao: Central South University
Zhengmao Hu: Central South University
Cindy Colson: EA7450 BioTARGen
Nicolas Richard: EA7450 BioTARGen
Charles E. Schwartz: Greenwood Genetic Center
Corrado Romano: Oasi Research Institute-IRCCS
Lucia Castiglia: Oasi Research Institute-IRCCS
Maria Bottitta: Oasi Research Institute-IRCCS
Shweta U. Dhar: Baylor College of Medicine
Deanna J. Erwin: Baylor College of Medicine
Lisa Emrick: Baylor College of Medicine
Boris Keren: Assistance Publique - Hôpitaux de Paris
Alexandra Afenjar: AP-HP, Hôpital Armand Trousseau
Baosheng Zhu: The First People’s Hospital of Yunnan Province
Bing Bai: The First People’s Hospital of Yunnan Province
Pawel Stankiewicz: Baylor College of Medicine
Kristin Herman: University of California, Davis
Saadet Mercimek-Andrews: The Hospital for Sick Children
Jane Juusola: GeneDx
Amy B. Wilfert: University of Washington School of Medicine
Rami Abou Jamra: University of Leipzig Medical Center
Benjamin Büttner: University of Leipzig Medical Center
Heather C. Mefford: University of Washington
Alison M. Muir: University of Washington
Ingrid E. Scheffer: Austin Health and Royal Children’s Hospital
Brigid M. Regan: Austin Health and Royal Children’s Hospital
Stephen Malone: Queensland Children’s Hospital
Jozef Gecz: The University of Adelaide at the Women’s and Children’s Hospital
Jan Cobben: Emma Children’s Hospital AUMC
Marjan M. Weiss: Vrije Universiteit Amsterdam, Department of Clinical Genetics
Quinten Waisfisz: Vrije Universiteit Amsterdam, Department of Clinical Genetics
Emilia K. Bijlsma: Leiden University Medical Center
Mariëtte J. V. Hoffer: Leiden University Medical Center
Claudia A. L. Ruivenkamp: Leiden University Medical Center
Stefano Sartori: University Hospital of Padua
Fan Xia: Baylor College of Medicine
Jill A. Rosenfeld: Baylor College of Medicine
Raphael A. Bernier: University of Washington
Michael F. Wangler: Baylor College of Medicine
Shinya Yamamoto: Baylor College of Medicine
Kun Xia: Central South University
Alexander P. A. Stegmann: Radboud University Medical Center
Hugo J. Bellen: Baylor College of Medicine
Alessandra Murgia: University of Padua
Evan E. Eichler: University of Washington School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2—whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.

Date: 2019
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DOI: 10.1038/s41467-019-12435-8

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