LAUSR

Dystonia is unusual, repetitive movements, postures, or both and is caused by sustained or episodic muscle contractions. Dystonia with childhood onset is often genetically determined. Recently, VPS16 has been identified as a causative gene for early-onset dystonia. We sought to further determine the spectrum and frequency of VPS16 variants in early-onset dystonia. We included 56 subjects (29 women and 27 men) of Chinese origin with dystonia onset before the age of 19 years (Supplementary Data). The median age of onset of dystonia was 12.2 years (range, 1–18). Patients who were suspected of acquired causes or positive for known dystoniaassociated genes through a gene panel (including 108 dystonia-related genes) were excluded. Whole-exome sequencing was performed to identify the pathogenic mutations in VPS16 and other genes related to dystonia. Written informed consent was obtained from all participating individuals or their legal guardians. One heterozygous frameshift variant (c.133_134dup, p. Pro46Alafs*6) in the VPS16 gene was identified in one pedigree. This variant was absent in 100 healthy controls or publicly available databases, such as the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/), Genome Aggregation Database (gnomAD, http://gnomad-old.broadinstitute.org/), and 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/variation/ tools/1000genomes/). The variant was predicted to be “disease causing” by MutationTaster and scored 32 by Combined Annotation Dependent Depletion (http://cadd.gs.washington.edu). It was rated as pathogenic according to the ACMG criterion (PVS1, PM2, and PP3). Segregation analysis confirmed that this variant was inherited from his father who did not show any abnormal symptoms at the current examination (Fig. 1). We also identified NKX2-1 (c.214_215insTACA, p. Arg72Tyrfs*30) and GNAO1 (c.644G>A, p. Cys215Tyr) mutations in 2 additional patients. The patient was a 30-year-old man from a nonconsanguineous family. He first experienced difficulty with writing when he was 9 years. During the following 21 years, he progressed to generalized dystonia with prominent bulbar, oromandibular, cervical, truck, and upper-limb involvement. Neither intellectual disability nor neuropsychiatric symptoms