BACKGROUND: Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems. However, the complete phenotypic spectrum of CHD8-related disorders is still undefined. In 2021, our group described two singular female patients with CHD8-related neurodevelopmental disorder and striking dystonic manifestations, prompting the suggestion that dystonia should be considered a possible component of this condition. CASE SERIES PRESENTATION: We describe three additional unrelated female individuals, each carrying a different CHD8 frameshift variant and whose clinical presentations were primarily characterized by young-onset dystonia. Their dystonic manifestations were remarkably heterogeneous and ranged from focal, exercise-dependent, apparently isolated forms to generalized permanent phenotypes accompanied by spasticity and tremor. Neurocognitive impairment and autistic behaviors, typical of CHD8-related disorders, were virtually absent or at the mild end of the spectrum. CONCLUSIONS: This work validates our previous observation that dystonia is part of the phenotypic spectrum of CHD8-related neurodevelopmental disorders with potential female preponderance, raising new challenges and opportunities in the diagnosis and management of this condition. It also highlights the importance of in-depth neurologic phenotyping of patients carrying variants associated with neurodevelopmental disorders, as the connection between neurodevelopmental and movement disorders is proving closer than previously appreciated.

Center for Rare Movement Disorders Innsbruck Department of Neurology Medical University of Innsbruck Innsbruck Austria

Cerebellar Malformations and Congenital Diseases Reference Center and Neurogenetics Lab Department of Genetics Armand Trousseau Hospital AP HP Sorbonne Université Paris France

Clinical Genetics Unit Department of Women's and Children's Health University of Padova Padua Italy

Department of Neurology and Centre of Clinical Neuroscience General University Hospital and 1st Faculty of Medicine Charles University Kateřinská 30 12 800 Prague Czech Republic

Developmental Brain Disorders Laboratory Imagine Institute INSERM UMR 1163 Paris France

DZPG Deutsches Zentrum Für Psychische Gesundheit Munich Germany

Institute for Advanced Study Technical University of Munich Garching Germany

Institute of Human Genetics School of Medicine Technical University of Munich Munich Germany

Institute of Neurogenomics Helmholtz Munich Neuherberg Germany

Munich Cluster for Systems Neurology Munich Germany

Sorbonne Université Service de Neuropédiatrie Pathologie du Développement Centre de Référence Neurogénétique Hôpital Trousseau AP HP SU HU I2D2 Paris France

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