Adult-onset dystonia associated with CHD8 truncating variants: case series and targeted literature review

The CHD8 gene encodes a chromatin-remodeling protein critical for neural development and transcriptional regulation. Although CHD8 mutations are classically associated with autism spectrum disorder, macrocephaly, and intellectual disability, recent reports suggest that dystonia may also be part of this spectrum. Two unrelated female patients presenting with progressive dystonia were evaluated through detailed clinical, neurological, and neuroimaging assessments. Whole exome sequencing (WES) was performed using the Twist Human Core Exome capture kit and variants were classified following American College of Medical Genetics and Genomics (ACMG) and Clingen SVI guidelines. A literature review was conducted to identify previously published CHD8 related dystonia cases. Patient 1 exhibited adult-onset segmental dystonia beginning at age 27, associated with macrocephaly and mild facial dysmorphism. Patient 2 developed generalized dystonia from adolescence, without cognitive or behavioral abnormalities. Pallidal deep brain stimulation produced marked motor improvement in Patient 1. Whole exome sequencing analyses revealed two heterozygous nonsense variants in the CHD8 gene NM_001170629.2:c.1444C>T (p.Arg482Ter) and NM_001170629.2:c.727C>T (p.Arg243Ter), respectively. Both variants were classified as likely pathogenic according to the current ACMG/ClinGen recommendations. These cases reinforce the evidence in the literature that CHD8 mutations are not only associated with neurodevelopmental disorders but may also cause isolated, adult-onset dystonia that is resistant to conventional pharmacological treatment, particularly in female patients.