Childhood onset dystonia, chorea or related movement disorder

Gene: VPS16

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 14 Mar 2022, 10:59 a.m. | Last Modified: 14 Mar 2022, 10:59 a.m.

Panel Version: 1.217

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 4:45 p.m. | Last Modified: 3 Mar 2022, 4:45 p.m.

Panel Version: 1.212

Green List (high evidence)

Penetrance for gene VPS16 was set from None to Incomplete - some variants transmitted from an unaffected parent and heterozygous LoF variants are observed in presumably healthy individuals in gnomAD

Created: 14 Jun 2021, 10:43 a.m. | Last Modified: 14 Jun 2021, 10:43 a.m.

Panel Version: 1.126

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 19 unrelated families reported with progressive dystonia (both multifocal and generalised types described) in association with variants in this gene (publications updated with relevant literature). Variable age of onset ranging from 3 to 50 years.

Created: 11 Jun 2021, 3:19 p.m. | Last Modified: 11 Jun 2021, 3:19 p.m.

Panel Version: 1.126

Comment on mode of inheritance: While most cases of VPS16-related dystonia have been due to heterozygous variants, one Chinese consanguineous family with dystonia has been found to harbour a homozygous missense variant (PMID:27174565). In view of only one biallelic case, MOI has been set as 'Monoallelic' - patients with biallelic variants would still be picked up by the Genomics England pipeline.

Furthermore, biallelic VPS16 variants have been linked to a mucopolysaccharidosis‐like disease - reviewed on the 'Lysosomal storage disorder' (R276) panel.

Created: 11 Jun 2021, 3:18 p.m. | Last Modified: 11 Jun 2021, 3:18 p.m.

Panel Version: 1.125

Green List (high evidence)

18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood.

Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals.
Sources: Literature

Created: 2 Nov 2020, 9:38 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Dystonia

Publications

• 32808683