Objective: To present an early-onset dystonia patient with a de novo VPS16 missense variant, along with molecular characterization.

Background: Mutations of the adaptor protein vacuolar protein sorting 16 homolog (VPS16) are a newly described cause of early-onset dystonia. Although mutation carriers have been reported in different populations, the mutational spectrum (truncating vs. missense; monoallelic vs. biallelic) in VPS16 remains largely elusive.

Method: The patient was identified among 182 patients with early-onset dystonia by Sanger sequencing. The genetic follow-up included testing for de-novo status by Sanger sequencing of both parents and confirmation of paternity by analysis of 7 microsatellite markers. Expression analyses were performed by qRT-PCR of RNA isolated from blood and cultured patient-derived fibroblasts. Electron microscopy was used to assess vacuolar abnormalities.

Results: We report a 56-year old German female patient with onset of lower limb dystonia at the age of 8 years and stepwise progression to involvement of the trunk, neck, face and all limbs along with severe dysarthria over the next ~25 years. No major psychiatric abnormalities were reported; family history was negative. A brain MRI showed minor nonspecific gliosis of the medullary layer. At the age of 42 years, the patient underwent bilateral deep brain stimulation (DBS) of the globus pallidus internus which led to overall reduction of symptoms. 
We identified a heterozygous missense variant in VPS16 (c.1189A>G, p.K397E). The variant was not found in the parents (de novo) and was novel (not listed in gnomAD or dbSNP). Pathogenicity was supported by a CADD score of 32. Expression of VPS16 was altered in blood and fibroblasts from the index patient compared to controls. Further, we detected vacuolar alterations using electron microscopy on patient-derived fibroblasts.

Conclusion: We here report the first dystonia patient with a de novo missense mutation in VPS16, the pathogenicity of which is strengthened by functional alterations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/molecular-changes-of-a-de-novo-missense-variant-in-vps16-in-dystonia/