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. van 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 Buettner; Heather C. Mefford; Alison M. Muir; Ingrid E. Scheffer; Brigid M. Regan; Stephen Malone; Jozef Gecz; Alexander P. A. Stegmann; University of Washington Center for Mendelian Genomics; Evan E. Eichler; Alessandra  Murgia

doi:10.1038/s41467-019-12435-8

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. van Bon, Tuula Rinne, Servi J. C. Stevens, Tjitske Kleefstra, Han G. Brunner, Helger G. YntemaMin 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 Buettner, Heather C. Mefford, Alison M. Muir, Ingrid E. Scheffer, Brigid M. Regan, Stephen Malone, Jozef Gecz, Alexander P. A. Stegmann, University of Washington Center for Mendelian Genomics, Evan E. Eichler^*, Alessandra Murgia^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	4679
Number of pages	17
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-12435-8
Publication status	Published - 15 Oct 2019

Keywords

DE-NOVO MUTATIONS
SYNAPTIC DEVELOPMENT
GENES
ANNOTATION
FRAMEWORK
RESOURCE
MEMORY

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Cite this

Guo, H., Bettella, E., Marcogliese, P. C., Zhao, R., Andrews, J. C., Nowakowski, T. J., Gillentine, M. A., Hoekzema, K., Wang, T., Wu, H., Jangam, S., Liu, C., Ni, H., Willemsen, M. H., van Bon, B. W., Rinne, T., Stevens, S. J. C., Kleefstra, T., Brunner, H. G., ... Murgia, A. (2019). Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders. Nature Communications, 10, Article 4679. https://doi.org/10.1038/s41467-019-12435-8

@article{10483f7ea8ef4cbfb19477e6926bd673,

title = "Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders",

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.",

keywords = "DE-NOVO MUTATIONS, SYNAPTIC DEVELOPMENT, GENES, ANNOTATION, FRAMEWORK, RESOURCE, MEMORY",

author = "Hui Guo and Elisa Bettella and Marcogliese, {Paul C.} and Rongjuan Zhao and Andrews, {Jonathan C.} and Nowakowski, {Tomasz J.} and Gillentine, {Madelyn A.} and Kendra Hoekzema and Tianyun Wang and Huidan Wu and Sharayu Jangam and Cenying Liu and Hailun Ni and Willemsen, {Marjolein H.} and {van Bon}, {Bregje W.} and Tuula Rinne and Stevens, {Servi J. C.} and Tjitske Kleefstra and Brunner, {Han G.} and Yntema, {Helger G.} and Min Long and Wenjing Zhao and Zhengmao Hu and Cindy Colson and Nicolas Richard and Schwartz, {Charles E.} and Corrado Romano and Lucia Castiglia and Maria Bottitta and Dhar, {Shweta U.} and Erwin, {Deanna J.} and Lisa Emrick and Boris Keren and Alexandra Afenjar and Baosheng Zhu and Bing Bai and Pawel Stankiewicz and Kristin Herman and Saadet Mercimek-Andrews and Jane Juusola and Wilfert, {Amy B.} and {Abou Jamra}, Rami and Benjamin Buettner and Mefford, {Heather C.} and Muir, {Alison M.} and Scheffer, {Ingrid E.} and Regan, {Brigid M.} and Stephen Malone and Jozef Gecz and Stegmann, {Alexander P. A.} and {University of Washington Center for Mendelian Genomics} and Eichler, {Evan E.} and Alessandra Murgia",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = oct,

day = "15",

doi = "10.1038/s41467-019-12435-8",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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Guo, H, Bettella, E, Marcogliese, PC, Zhao, R, Andrews, JC, Nowakowski, TJ, Gillentine, MA, Hoekzema, K, Wang, T, Wu, H, Jangam, S, Liu, C, Ni, H, Willemsen, MH, van Bon, BW, Rinne, T, Stevens, SJC, Kleefstra, T, Brunner, HG, Yntema, HG, Long, M, Zhao, W, Hu, Z, Colson, C, Richard, N, Schwartz, CE, Romano, C, Castiglia, L, Bottitta, M, Dhar, SU, Erwin, DJ, Emrick, L, Keren, B, Afenjar, A, Zhu, B, Bai, B, Stankiewicz, P, Herman, K, Mercimek-Andrews, S, Juusola, J, Wilfert, AB, Abou Jamra, R, Buettner, B, Mefford, HC, Muir, AM, Scheffer, IE, Regan, BM, Malone, S, Gecz, J, Stegmann, APA, University of Washington Center for Mendelian Genomics, Eichler, EE & Murgia, A 2019, 'Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders', Nature Communications, vol. 10, 4679. https://doi.org/10.1038/s41467-019-12435-8

TY - JOUR

T1 - Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders

AU - Guo, Hui

AU - Bettella, Elisa

AU - Marcogliese, Paul C.

AU - Zhao, Rongjuan

AU - Andrews, Jonathan C.

AU - Nowakowski, Tomasz J.

AU - Gillentine, Madelyn A.

AU - Hoekzema, Kendra

AU - Wang, Tianyun

AU - Wu, Huidan

AU - Jangam, Sharayu

AU - Liu, Cenying

AU - Ni, Hailun

AU - Willemsen, Marjolein H.

AU - van Bon, Bregje W.

AU - Rinne, Tuula

AU - Stevens, Servi J. C.

AU - Kleefstra, Tjitske

AU - Brunner, Han G.

AU - Yntema, Helger G.

AU - Long, Min

AU - Zhao, Wenjing

AU - Hu, Zhengmao

AU - Colson, Cindy

AU - Richard, Nicolas

AU - Schwartz, Charles E.

AU - Romano, Corrado

AU - Castiglia, Lucia

AU - Bottitta, Maria

AU - Dhar, Shweta U.

AU - Erwin, Deanna J.

AU - Emrick, Lisa

AU - Keren, Boris

AU - Afenjar, Alexandra

AU - Zhu, Baosheng

AU - Bai, Bing

AU - Stankiewicz, Pawel

AU - Herman, Kristin

AU - Mercimek-Andrews, Saadet

AU - Juusola, Jane

AU - Wilfert, Amy B.

AU - Abou Jamra, Rami

AU - Buettner, Benjamin

AU - Mefford, Heather C.

AU - Muir, Alison M.

AU - Scheffer, Ingrid E.

AU - Regan, Brigid M.

AU - Malone, Stephen

AU - Gecz, Jozef

AU - Stegmann, Alexander P. A.

AU - University of Washington Center for Mendelian Genomics

AU - Eichler, Evan E.

AU - Murgia, Alessandra

PY - 2019/10/15

Y1 - 2019/10/15

N2 - 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.

AB - 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.

KW - DE-NOVO MUTATIONS

KW - SYNAPTIC DEVELOPMENT

KW - GENES

KW - ANNOTATION

KW - FRAMEWORK

KW - RESOURCE

KW - MEMORY

U2 - 10.1038/s41467-019-12435-8

DO - 10.1038/s41467-019-12435-8

M3 - Article

C2 - 31616000

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 4679

ER -