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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.

SUBMITTER: Guo H

PROVIDER: S-EPMC6794285 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Guo Hui H Bettella Elisa E Marcogliese Paul C PC Zhao Rongjuan R Andrews Jonathan C JC Nowakowski Tomasz J TJ Gillentine Madelyn A MA Hoekzema Kendra K Wang Tianyun T Wu Huidan H Jangam Sharayu S Liu Cenying C Ni Hailun H Willemsen Marjolein H MH van Bon Bregje W BW Rinne Tuula T Stevens Servi J C SJC Kleefstra Tjitske T Brunner Han G HG Yntema Helger G HG Long Min M Zhao Wenjing W Hu Zhengmao Z Colson Cindy C Richard Nicolas N Schwartz Charles E CE Romano Corrado C Castiglia Lucia L Bottitta Maria M Dhar Shweta U SU Erwin Deanna J DJ Emrick Lisa L Keren Boris B Afenjar Alexandra A Zhu Baosheng B Bai Bing B Stankiewicz Pawel P Herman Kristin K Mercimek-Andrews Saadet S Juusola Jane J Wilfert Amy B AB Abou Jamra Rami R Büttner Benjamin B Mefford Heather C HC Muir Alison M AM Scheffer Ingrid E IE Regan Brigid M BM Malone Stephen S Gecz Jozef J Cobben Jan J Weiss Marjan M MM Waisfisz Quinten Q Bijlsma Emilia K EK Hoffer Mariëtte J V MJV Ruivenkamp Claudia A L CAL Sartori Stefano S Xia Fan F Rosenfeld Jill A JA Bernier Raphael A RA Wangler Michael F MF Yamamoto Shinya S Xia Kun K Stegmann Alexander P A APA Bellen Hugo J HJ Murgia Alessandra A Eichler Evan E EE

Nature communications 20191015 1

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 dysmo ...[more]

PMID: 31616000

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Project description:Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype-phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.

Dataset Information

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

Publications

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

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