LAUSR

sensory examination, and cognitive functions were normal. The patient was able to walk without support but with extensor trunk posture. Brain and cervical spine magnetic resonance imaging was normal. To identify the disease-causing gene, we carried out highdensity single-nucleotide polymorphism genome-wide genotyping in all DNA samples available from the family and whole-exome sequencing (WES) in the patient. We ran linkage analysis assuming an autosomal recessive mode of inheritance and parental consanguinity, which yielded a list of candidate genomic regions (Supporting Information Appendix S1). By inspecting the WES data of the patient for rare homozygous variants with predicted coding or splicing effect (Supporting Information Appendix S1), we identified a 70-nucleotide duplication in exon 2 of AOPEP (NM_ 001193329.1), leading to premature termination in the encoded protein: c.333_402dup (p.Gly135*). This variant is absent in gnomAD. Agarose gel electrophoresis (Fig. 1B), as well as Sanger sequencing (Fig. 1C), confirmed the variant and showed its presence in homozygous state in the affected subject but in none of his unaffected relatives. Furthermore, WES analysis demonstrated no definitive disease-causing variants in other known dystonia genes, nor compelling variants in other genes in the candidate genomic regions (Supporting Information Appendix S1). We therefore consider the novel LOF AOPEP variant (Fig. 1D) as disease causing in this patient. The recently described cases presented with progressive dystonia, predominantly involving upper and lower limbs, with variable involvement of craniocervical and truncal districts. The age at onset ranged from childhood to early adulthood. In three of the four families reported, dystonia was isolated. Our patient also manifested dystonia in the upper limbs in early adulthood, which progressed to the craniocervical and truncal segments. This work provides further, independent evidence for the involvement of AOPEP in early-onset dystonia. Future clinical studies will contribute to better delineating the phenotypic spectrum of AOPEP-related dystonia, while functional work is warranted to provide insights into the mechanisms by which AOPEP LOF leads to dystonia.