Journal Article

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

Scheffer, Ingrid E., Ruivenkamp, Claudia A. L., Mercimek-Andrews, Saadet, Wang, Tianyun, Bellen, Hugo J., Hoffer, Mariëtte J. V., Wu, Huidan, Colson, Cindy, Büttner, Benjamin, Abou Jamra, Rami, Xia, Kun, Yamamoto, Shinya, Malone, Stephen, Sartori, Stefano, Wangler, Michael F., Jangam, Sharayu, Brunner, Han G., Zhao, Rongjuan, Hu, Zhengmao, Weiss, Marjan M., Schwartz, Charles E., Afenjar, Alexandra, Keren, Boris, Herman, Kristin, Rosenfeld, Jill A., Bottitta, Maria, Regan, Brigid M., Gecz, Jozef, Cobben, Jan, Zhu, Baosheng, Waisfisz, Quinten, Ni, Hailun, Dhar, Shweta U., Bijlsma, Emilia K., Marcogliese, Paul C., Bernier, Raphael A., Gillentine, Madelyn A., Long, Min, Richard, Nicolas, Rinne, Tuula, Romano, Corrado, Muir, Alison M., Stankiewicz, Pawel, Wilfert, Amy B., Willemsen, Marjolein H., Juusola, Jane, Stegmann, Alexander P. A., Andrews, Jonathan C., Castiglia, Lucia, Emrick, Lisa, Xia, Fan, van Bon, Bregje W., Kleefstra, Tjitske, Hoekzema, Kendra, Stevens, Servi J. C., Bai, Bing, Yntema, Helger G., Liu, Cenying, Eichler, Evan E., Zhao, Wenjing, Guo, Hui, Mefford, Heather C., Nowakowski, Tomasz J., Bettel

2019

Overview

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. Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols , the TANC2 homolog in flies, is required for synapse growth and function.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/44 / 13/89 / 14/1 / 14/19 / 38/39 / 45/23 / 631/208/1515 / 631/378/2571/1696 / 631/378/2583 / 64/24 / 692/617/375/366 / Adolescent / Adult / Animals / Autism / Autistic Disorder - genetics / Autistic Disorder - psychology / Behavior, Animal / Brain - metabolism / Child / Child, Preschool / Craniofacial Abnormalities - genetics / Developmental Disabilities - genetics / Developmental Disabilities - psychology / Disorders / Disruption / Drosophila melanogaster / Drosophila Proteins - genetics / Drosophila Proteins - metabolism / Epilepsy / Epilepsy - genetics / Exome Sequencing / Female / Fruit flies / Genetics / Glial cells / Human genetics / Humanities and Social Sciences / Humans / Intellectual Disability - genetics / Intellectual Disability - psychology / Language Development Disorders - genetics / Language Development Disorders - psychology / Life Sciences / Male / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mental disorders / Mental Disorders - genetics / Mental Disorders - psychology / multidisciplinary / Muscle Proteins - genetics / Muscle Proteins - metabolism / Mutation / Nerve Tissue Proteins - metabolism / Neurodevelopmental disorders / Neurodevelopmental Disorders - genetics / Neurodevelopmental Disorders - psychology / Neuroglia - metabolism / Neuronal-glial interactions / Neurons - metabolism / Patients / Postsynaptic density / Proteins / Proteins - genetics / Proteins - metabolism / Science / Science (multidisciplinary) / Young Adult