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.

Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

“…Finally, one mother who transmitted a splice acceptor variant (c.1189-2 A > G) in TCF12 was diagnosed with long QT syndrome and glaucoma (like the patient) but this shared feature is unlikely related to DD observed in the child or the variant in question. These findings are consistent with the idea that such transmitted variants are by themselves not necessary and sufficient to develop DD but may rather be predisposing variants with a subset of parents manifesting more subtle phenotypes 23 .…”

BAZ2B haploinsufficiency as a cause of developmental delay, intellectual disability, and autism spectrum disorder

“…BAZ2B was recently prioritized as a potential candidate gene for autism spectrum disorder (ASD) by Guo et al (2019) based on the analysis of exome sequencing data from large, family‐based, exome sequencing studies (De Rubeis et al, 2014; Fischbach & Lord, 2010). Loss of BAZ2B function has also been postulated to contribute to the development of neurodevelopmental disorders in humans (Deciphering Developmental Disorders, 2017; Iossifov et al, 2014; Krupp et al, 2017; Lelieveld et al, 2016) based on the identification of de novo and mosaic BAZ2B variants in individuals with these disorders.…”

Tanc2-dependent direct and regulated mTOR inhibition balances mTORC1/2 signaling in developing mouse and human neurons

“…anti-sense Tanc2 knockdown or virusmediated Tanc2 overexpression, could be used to treat various mTOR-related brain disorders 5-7,37−39 . These therapeutic potentials extend to non-neural tissues and non-brain mTOR-related disorders such as metabolic diseases 1,2 because Tanc2 and Tanc1 are expressed in various non-neural tissues in mice and humans (www.ebi.ac.uk/gxa/home) 16,17 .…”

“…Tanc2, a large (~ 200 kDa) multi-domain adaptor/scaffolding protein, is highly expressed in the brain 15,16 and modestly expressed in other tissues (www.ebi.ac.uk/gxa/home) 17 . Tanc2 is present at both synaptic and non-synaptic sites in neurons.…”

“…In humans, TANC2 mutations are extensively associated with various neuropsychiatric disorders, including intellectual disability, ASD, developmental delays, and schizophrenia 17,22−30 . Disruptive TANC2 mutations were recently identi ed in 20 different patients with neurodevelopmental symptoms associated with psychiatric disorders 17 . These results suggest that Tanc2 is a critical regulator of brain development and function, but the underlying mechanisms remain unclear.…”