Single Molecule Molecular Inversion Probes for High Throughput Germline Screenings in Dystonia.

This study's aim was to investigate a large cohort of dystonia patients for pathogenic and rare variants in the gene, making use of a new, cost-efficient enrichment technology for NGS-based screening. Single molecule Molecular Inversion Probes (smMIPs) were used for targeted enrichment and sequencing of all protein coding exons and exon-intron boundaries of the gene in 373 dystonia patients and six positive controls with known variants. Additionally, a rare-variant association study was performed.

Needs and Requirements of Modern Biobanks on the Example of Dystonia Syndromes.

Dystonia belongs to a group of rare diseases (RDs) characterized by etiologic heterogeneity, affection often in childhood, severe and variable clinical manifestation. The burden of this disease is aggravated by the lack of effective and specific treatment. In the field of dystonia as in other RDs the number of available biospecimens is, in general, limited.

HBOC multi-gene panel testing: comparison of two sequencing centers.

Multi-gene panels are used to identify genetic causes of hereditary breast and ovarian cancer (HBOC) in large patient cohorts. This study compares the diagnostic workflow in two centers and gives valuable insights into different next-generation sequencing (NGS) strategies. Moreover, we present data from 620 patients sequenced at both centers.

Biochemical and cellular analysis of human variants of the DYT1 dystonia protein, TorsinA/TOR1A.

Early-onset dystonia is associated with the deletion of one of a pair of glutamic acid residues (c.904_906delGAG/c.907_909delGAG; p.

Combined occurrence of a novel TOR1A and a THAP1 mutation in primary dystonia.

Background: The ΔGAG deletion of the TOR1A gene (DYT1) is responsible for DYT1 dystonia. However, no other TOR1A mutation has been reported in the Chinese population.

Methods: Two hundred one dystonia patients without the ΔGAG deletion were screened for other mutations in TOR1A.

Screening of mutations in GNAL in sporadic dystonia patients.

Background: GNAL mutations have been shown to cause adult-onset isolated dystonia, a disabling movement disorder characterized by involuntary muscle contractions causing twisting and repetitive movements or abnormal postures.

Methods: To test the frequency of GNAL mutations in a series of 137 German patients with sporadic dystonia patients we used next-generation sequencing of amplicon-derived barcoded NexteraXT libraries for the coding exons and adjacent intronic sequences of GNAL.

Results: In our cohort we identified 1 pathogenic nonsense mutation (c.

New genetic insights highlight 'old' ideas on motor dysfunction in dystonia.

Primary dystonia is a poorly understood but common movement disorder. Recently, several new primary dystonia genes were identified that provide new insight into dystonia pathogenesis. The GNAL dystonia gene is central for striatal responses to dopamine (DA) and is a component of a molecular pathway already implicated in DOPA-responsive dystonia (DRD).

Generation of a novel rodent model for DYT1 dystonia.

A mutation in the coding region of the Tor1A gene, resulting in a deletion of a glutamic acid residue in the torsinA protein (∆ETorA), is the major cause of the inherited autosomal-dominant early onset torsion dystonia (DYT1). The pathophysiological consequences of this amino acid loss are still not understood. Currently available animal models for DYT1 dystonia provided important insights into the disease; however, they differ with respect to key features of torsinA associated pathology.

Prevalence of THAP1 sequence variants in German patients with primary dystonia.

Primary dystonias are a clinically and genetically heterogeneous group of movement disorders, but only for two of them, i.e., dystonia 1 and dystonia 6, the disease causing gene has been identified.

Adult neural precursor cells unaffected in animal models of DYT1 dystonia.

Hereditary dystonias in humans are frequently related to a specific mutation of the DYT1 gene that encodes torsinA. This mutation has been shown to disrupt neuronal cell migration during development. We compared adult neurogenesis, occurring in the hippocampus and the olfactory bulb, in transgenic mice overexpressing either the wild-type or mutant form of human torsinA.

Gene expression changes in a transgenic mouse model overexpressing human wildtype and mutant torsinA.

Primary torsion dystonia is an autosomal-dominantly inherited, neurodevelopmental movement disorder caused by a GAG deletion (ΔGAG) in the DYT1 gene, encoding torsinA. This mutation is responsible for approximately 70% of cases of early-onset primary torsion dystonia. The function of wildtype torsinA is still unknown, and it is unsolved how the deletion in the DYT1 gene contributes to the development of the disease.

Mutation at the SCA17 locus is not a common cause of primary dystonia.

Spinocerebellar ataxia type 17 (SCA17) is a dominant progressive neurodegenerative disorder, caused by a triplet repeat expansion within the TATA-binding protein. As well as ataxia and dementia, Parkinsonism and dystonia are common in SCA17. In some pedigrees focal dystonia in the absence of ataxia has been described as a main clinical feature.

Lack of mutations in the epsilon-sarcoglycan gene in patients with different subtypes of primary dystonias.

Primary dystonias represent a clinically and genetically heterogeneous group of movement disorders. Mutations in the epsilon-sarcoglycan (SGCE) gene have been found recently to cause myoclonus-dystonia (MD). Considerable clinical variation of SGCE mutation carriers leads to the hypothesis that mutations in the SGCE gene might also be relevant for other subtypes of dystonias.

Frequency and phenotypic variability of the GAG deletion of the DYT1 gene in an unselected group of patients with dystonia.

Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures. A 3-base pair (GAG) deletion in the DYT1 gene is held responsible for most cases of early-onset primary generalized dystonia in the Ashkenazi Jewish population as well as in non-Jewish patients.

Objectives: To investigate the prevalence of the GAG deletion in the DYT1 gene and the phenotypic variability in the general population by testing patients with different subtypes of dystonia from 4 different movement disorder outpatient clinics in Germany.