51. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.
- Author
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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, Büttner B, Mefford HC, Muir AM, Scheffer IE, Regan BM, Malone S, Gecz J, Cobben J, Weiss MM, Waisfisz Q, Bijlsma EK, Hoffer MJV, Ruivenkamp CAL, Sartori S, Xia F, Rosenfeld JA, Bernier RA, Wangler MF, Yamamoto S, Xia K, Stegmann APA, Bellen HJ, Murgia A, and Eichler EE
- Subjects
- Adolescent, Adult, Animals, Autistic Disorder genetics, Autistic Disorder psychology, Behavior, Animal, Brain metabolism, Child, Child, Preschool, Craniofacial Abnormalities genetics, Developmental Disabilities genetics, Developmental Disabilities psychology, Drosophila Proteins genetics, Drosophila Proteins metabolism, Drosophila melanogaster, Epilepsy genetics, Female, Humans, Intellectual Disability genetics, Intellectual Disability psychology, Language Development Disorders genetics, Language Development Disorders psychology, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mental Disorders psychology, Muscle Proteins genetics, Muscle Proteins metabolism, Mutation, Neurodevelopmental Disorders psychology, Neuroglia metabolism, Neurons metabolism, Proteins metabolism, Exome Sequencing, Young Adult, Mental Disorders genetics, Nerve Tissue Proteins metabolism, Neurodevelopmental Disorders genetics, Proteins genetics
- 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.
- Published
- 2019
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