Functional Evaluations of Genes Disrupted in Patients with Tourette's Disorder

Abstract

Tourette's disorder (TD) is a highly heritable neurodevelopmental disorder with complex genetic architecture and unclear neuropathology. Disruptions of particular genes have been identified in subsets of TD patients. However, none of the findings have been replicated, probably due to the complex and heterogeneous genetic architecture of TD that involves both common and rare variants. To understand the etiology of TD, functional analyses are required to characterize the molecular and cellular consequences caused by mutations in candidate genes. Such molecular and cellular alterations may converge into common biological pathways underlying the heterogeneous genetic etiology of TD patients. Herein, we review specific genes implicated in TD etiology, discuss the functions of these genes in the mammalian central nervous system and the corresponding behavioral anomalies exhibited in animal models, and importantly, review functional analyses that can be performed to evaluate the role(s) that the genetic disruptions might play in TD. Specifically, the functional assays include novel cell culture systems, genome editing techniques, bioinformatics approaches, transcriptomic analyses, and genetically modified animal models applied or developed to study genes associated with TD or with other neurodevelopmental and neuropsychiatric disorders. By describing methods used to study diseases with genetic architecture similar to TD, we hope to develop a systematic framework for investigating the etiology of TD and related disorders.

Keywords: Tourette’s disorder; functional studies; genes; induced pluripotent stem cells; neurobiology.