Objective: To further clarify the spectrum and frequency of ANO3 rare variants in Chinese populations with primary dystonia.

Background: Dystonia is a movement disorder with high clinical and genetic heterogeneity. The rare variants in ANO3 have been recognized as an important cause of dystonia 24 (DYT24) and developed a broad phenotypic spectrum ranging from cranio-cervical dystonia to limb dystonia, and combined dystonia involving myoclonus, parkinsonism. As the various phenotypes and relatively high frequency in healthy individuals, the role of ANO3 variants in dystonia is under debate.

Method: Sanger sequencing was used to screen all exons and exon-intron boundaries of ANO3 for rare variants in 116 dystonia patients. Pathogenicity of detected variants were assessed by in silico algorithms. The clinical manifestations of patients with ANO3 variants in our study and previously reported literatures were further characterized.

Results: There are 6 different rare variants of ANO3 gene identified, including two missense variants (c.1127A>G, p.Tyr376Cys; c.1235T>A, p.Val412Asp) with high pathogenicity in silico analysis, two synonymous variants (c.339G>A, p.Thr113Thr; c.1380T>C, p.Tyr460Tyr), and one variant in splice region (c.1531-3T>C) or 5’ UTR (c.-11G>T), in 8 individuals. Regardless of the synonymous variant carriers, the rare variants of ANO3 were found in 5.17% (6/116) cases. The average age at onset was 57.83±7.76 years (age ranging from 46 to 67 years). All variants carriers presented with cranio-cervical dystonia. Cervical dystonia (66.6%) is the most common phenotype, then follows blepharospasm (50%). Only 1 case developed limb dystonia and no combined dystonia cases were mentioned. To date, 31 different rare variants were identified in 58 dystonia patients. The age of onset ranged from 1 to 69 years and peaked in late adulthood (about 40%). The predominant phenotype is cranio-cervical dystonia. Most of patients presented with isolated dystonia whereas few of them showed combined dystonia.

Conclusion: This study confirms a relatively high frequency of rare ANO3 variants in Chinese patients with sporadic dystonia and indicates that the late adulthood-onset, cranio-cervical dystonia seems to be an important feature of the ANO3 phenotype. Further functional studies are warranted to understand the role of ANO3 in dystonia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/frequency-and-phenotypic-spectrum-of-ano3-dystonia-a-single-center-cohort-study/