Genetic intersection between dystonia and neurodevelopmental disorders: Insights from genomic sequencing

Animal and human brain-imaging studies have suggested a role for neurodevelopmental abnormalities in the pathophysiology of dystonia. Variants in neurodevelopmental genes have also been sporadically implicated, although no systematic investigation has been undertaken before the more widespread availability of genome-wide sequencing techniques. Here, we review findings from recent whole-exome and whole-genome sequencing approaches in individuals with dystonic conditions, indicating that more than 50% of molecularly diagnosed cases may have variants in neurodevelopmental disorder-associated genes. We describe how genomic sequencing has contributed to phenotypic expansions of several known hereditary forms of dystonia to include classical neurodevelopmental features. Moreover, we demonstrate that many of the newly reported monogenic neurodevelopmental disorders can manifest with prominent dystonic presentations, including isolated general-ized dystonia, paroxysmal dystonia, and dopa-responsive dystonia-parkinsonism. Considering the published evidence, we argue that the clinical feature dystonia might be regarded as an expression of developmental brain dysfunction, a status referring to the common etiological basis of many neurodevelopmental disease traits. Finally, we provide a view into clinical implications, including the necessity to integrate the interrogation of neurodevelopmental disorder-associated genes into the molecular analysis process of patients with dystonia. Recognizing the relationship between dystonia and neurodevelopmental disorders is important to improve pa-tient counseling and management and develop novel therapeutic strategies.

Automated summary

Recent studies have found that neurodevelopmental abnormalities play a role in the pathophysiology of dystonia. Through whole-exome and whole-genome sequencing techniques, it has been discovered that over 50% of molecularly diagnosed dystonia cases may have variants in neurodevelopmental disorder-associated genes. Additionally, it has been shown that many newly reported monogenic neurodevelopmental disorders can present with prominent dystonic symptoms. These findings suggest that dystonia may be considered an expression of developmental brain dysfunction, highlighting the relationship between dystonia and neurodevelopmental disorders.