Dataset Information

Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

ABSTRACT:

Background

VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization.

Cases

We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoathetosis, pharyngospasm and freezing of gait. Response to bilateral Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) is reported in three of them, associated with significant improvement of dystonia but only minor effect on other hyperkinetic movements. Moreover, five novel pathogenic/likely pathogenic variants are described.

Conclusions

This case collection expands the genetic and clinical spectrum of VPS16-related disease, prompting movement disorder specialists to suspect mutations of this gene not only in patients with isolated dystonia.

SUBMITTER: Monfrini E

PROVIDER: S-EPMC10828607 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

Monfrini Edoardo E Avanzino Laura L Palermo Giovanni G Bonato Giulia G Brescia Gloria G Ceravolo Roberto R Cantarella Giovanna G Mandich Paola P Prokisch Holger H Storm Van's Gravesande Karin K Straccia Giulia G Elia Antonio A Reale Chiara C Panteghini Celeste C Zorzi Giovanna G Eleopra Roberto R Erro Roberto R Carecchio Miryam M Garavaglia Barbara B Zech Michael M Romito Luigi L Di Fonzo Alessio A

Movement disorders clinical practice 20231212 1

<h4>Background</h4>VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization.<h4>Cases</h4>We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoatheto ...[more]

PMID: 38291845

Similar Datasets

Project description:Background and objectivesOur objective was to improve rare variant interpretation using statistical measures as well as publicly accessible annotation of expression levels and tissue specificity of different splice isoforms. We describe rare VPS16 variants observed in patients with dystonia and patients without dystonia, elaborate on our interpretation of VPS16 variants affecting different transcripts, and provide detailed clinical description of the movement disorder caused by VPS16 variants.MethodsIn-house exome and genome data sets (n = 11,539) were screened for rare heterozygous missense and putative loss-of-function (pLoF) variants in VPS16. Using pext (proportion expressed across transcripts) values from the Genome Aggregation Database (gnomAD), we differentiated variants affecting weakly and highly expressed exons/transcripts and applied statistical measures to systematically identify disease-associated genetic variation among patients with dystonia (n = 280).ResultsSix different heterozygous pLoFs in VPS16 transcripts were identified in 13 individuals. Three of these pLoFs occurred in 9 individuals with different phenotypes, and 3 pLoFs were identified in 4 unrelated individuals with early-onset dystonia. Although pLoFs were enriched in the dystonia cohort (n = 280; p = 2.04 × 10-4; 4/280 cases vs 9/11,259 controls; Fisher exact test), it was not exome-wide significant. According to the pext values in gnomAD, all 3 pLoFs observed in the patients with dystonia were located in the highly expressed canonical transcript ENST00000380445.3, whereas 2 of 3 pLoFs detected in 8 individuals without dystonia were located in the first exon of the noncanonical transcript ENST00000380443.3 that is weakly expressed across all tissues. Taking these biological implications into account, pLoFs involving the canonical transcript were exome-wide significantly enriched in patients with dystonia (p = 1.67 × 10-6; 4/280 cases vs 1/11,259 controls; Fisher exact test). All VPS16 patients showed mild progressive dystonia with writer's cramp as the presenting symptom between age 7 and 34 years (mean 20 years) that often progressed to generalized dystonia and was even accompanied by hyperkinetic movements and myoclonus in 1 patient.DiscussionOur data provide strong evidence for VPS16 pLoFs to be implicated in dystonia and knowledge on exon resolution expression levels as well as statistical measures proved to be useful for variant interpretation.

Dataset Information

Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

Background

Cases

Conclusions

Publications

Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets