2. Academic Validation
  3. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders

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

  • Nat Commun. 2019 Oct 15;10(1):4679. doi: 10.1038/s41467-019-12435-8.
Hui Guo 1 2,  Elisa Bettella 3 4,  Paul C Marcogliese 5 6,  Rongjuan Zhao 2,  Jonathan C Andrews 5 6,  Tomasz J Nowakowski 7 8 9,  Madelyn A Gillentine 1,  Kendra Hoekzema 1,  Tianyun Wang 1 2,  Huidan Wu 2,  Sharayu Jangam 5 6,  Cenying Liu 2,  Hailun Ni 2,  Marjolein H Willemsen 10 11,  Bregje W van Bon 10,  Tuula Rinne 10,  Servi J C Stevens 11,  Tjitske Kleefstra 10,  Han G Brunner 10 11,  Helger G Yntema 10,  Min Long 2,  Wenjing Zhao 2,  Zhengmao Hu 2,  Cindy Colson 12,  Nicolas Richard 12,  Charles E Schwartz 13,  Corrado Romano 14,  Lucia Castiglia 14,  Maria Bottitta 14,  Shweta U Dhar 5,  Deanna J Erwin 5,  Lisa Emrick 5,  Boris Keren 15,  Alexandra Afenjar 16,  Baosheng Zhu 17 18,  Bing Bai 17 18,  Pawel Stankiewicz 5,  Kristin Herman 19,  University of Washington Center for Mendelian Genomics,  Saadet Mercimek-Andrews 20,  Jane Juusola 21,  Amy B Wilfert 1,  Rami Abou Jamra 22,  Benjamin Büttner 22,  Heather C Mefford 23,  Alison M Muir 23,  Ingrid E Scheffer 24,  Brigid M Regan 24,  Stephen Malone 25,  Jozef Gecz 26,  Jan Cobben 27 28,  Marjan M Weiss 29,  Quinten Waisfisz 29,  Emilia K Bijlsma 30,  Mariëtte J V Hoffer 30,  Claudia A L Ruivenkamp 30,  Stefano Sartori 31,  Fan Xia 5,  Jill A Rosenfeld 5,  Raphael A Bernier 32,  Michael F Wangler 5 6 33,  Shinya Yamamoto 5 6 33 34,  Kun Xia 2 35,  Alexander P A Stegmann 10 11,  Hugo J Bellen 5 6 33 34 36,  Alessandra Murgia 37,  Evan E Eichler 38 39
Affiliations

Affiliations

  • 1 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.
  • 2 Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 410078, Changsha, Hunan, China.
  • 3 Laboratory of Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padua, Via Giustiniani 3, 35128, Padua, Italy.
  • 4 Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Corso Stati Uniti 4, 35129, Padua, Italy.
  • 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 6 Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, 77030, USA.
  • 7 UCSF Department of Anatomy, University of California, San Francisco, San Francisco, CA, 94143, USA.
  • 8 UCSF Department of Psychiatry, University of California, San Francisco, San Francisco, CA, 94143, USA.
  • 9 UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, 94158, USA.
  • 10 Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
  • 11 Department of Clinical Genetics, Maastricht University Medical Center, 6202 AZ, Maastricht, The Netherlands.
  • 12 Normandie Univ, UNICAEN, CHU de Caen Normandie, Department of Genetics, EA7450 BioTARGen, 14000, Caen, France.
  • 13 Greenwood Genetic Center, Greenwood, SC, 29646, USA.
  • 14 Oasi Research Institute-IRCCS, 94108, Troina, Italy.
  • 15 Département de génétique, Hôpital Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013, Paris, France.
  • 16 APHP, Centre de référence des malformations et maladies congénitales du cervelet Département de génétique et embryologie médicale, GRCn°19, pathologies Congénitales du Cervelet-LeucoDystrophies, AP-HP, Hôpital Armand Trousseau, F-75012, Paris, France.
  • 17 Department of Pediatrics, The First People's Hospital of Yunnan Province, 650032, Kunming, Yunnan, China.
  • 18 Medical Faculty, Kunming University of Science and Technology, 650032, Kunming, Yunnan, China.
  • 19 Section of Medical Genomics, Medical Investigation of Neurodevelopmental Disorders Institute, University of California, Davis, Sacramento, CA, 95817, USA.
  • 20 Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
  • 21 GeneDx, Gaithersburg, MD, 20877, USA.
  • 22 Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
  • 23 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, 98195, USA.
  • 24 Departments of Medicine and Paediatrics, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, 3084, Australia.
  • 25 Department of Neurosciences, Queensland Children's Hospital, Brisbane, QLD, 4101, Australia.
  • 26 School of Medicine and the Robinson Research Institute, The University of Adelaide at the Women's and Children's Hospital, Adelaide, SA, 5006, Australia.
  • 27 Emma Children's Hospital AUMC, 1105 AZ, Amsterdam, The Netherlands.
  • 28 North West Thames Genetics Service NHS, London, UK.
  • 29 Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Clinical Genetics, Amsterdam, Netherlands.
  • 30 Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
  • 31 Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padua, 35128, Padua, Italy.
  • 32 Department of Psychiatry, University of Washington, Seattle, WA, 98195, USA.
  • 33 Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 34 Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 35 Hunan Key Laboratory of Animal Models for Human Diseases, 410078, Changsha, Hunan, China.
  • 36 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 37 Laboratory of Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padua, Via Giustiniani 3, 35128, Padua, Italy. alessandra.murgia@unipd.it.
  • 38 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA. eee@gs.washington.edu.
  • 39 Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, USA. eee@gs.washington.edu.
PMID: 31616000 DOI: 10.1038/s41467-019-12435-8
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.

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