Genomic profiling of adult-onset isolated focal dystonia in a group of Romanian patients (GENDYS)

GENDYS is a research project supported by a grant of the Romanian Ministery of Research and Innovation, CNCS - UEFISCDI, project number PN-III-P4-ID-PCE-2016-0696, contract no. 159/07.2017, PNCDI III, LS5_2 - Molecular and cellular neuroscience

GENDYS uses targeted and whole exome Next Generation Sequencing for identifying pathogenic gene variants that contribute to the development of adult-onset isolated focal dystonia in Romanian patients and putative genes yet unknown to be related to this type of disorders – SEE THE CURRENT STATUS OF THE PROJECT below (last update 26.09.19).

ABSTRACT OF THE PROJECT:

Isolated focal dystonia is the most common movement disorder after Parkinson disease and essential tremor. Is relatively rare, but may be highly debilitating. No preventive or disease modifying treatments are available. Symptomatic treatments are only modestly effective. The typical onset is in adulthood. The etiology is genetic in some cases, but over 75% are idiopathic. Whole exome sequencing (WES) has been successfully used in the recent years for finding rare disease-causing alleles. Compared with more traditional approaches this method successfully identified several dystonia-related genes. Our project proposes to identify relevant genomic profiles by WES, replicate previously published results and test the usefulness of targeted next-generation sequencing as a sensitive and accurate tool for the simultaneous screening of dystonia. Our objectives will be reached in two steps by: 1) screening a well described homogenous group of Romanian dystonia cases (n=120, i.e. moderate size) and controls (n=97) using our own designed targeted sequencing panel of previously isolated dystonia-associated genes (DYTs) and 2) identifying of new gene/variants related to the disease by analyzing the negative-known DYTs subjects using a high-throughput sequencing approach. The potential gene interactions will be evaluated by logistic regression analyses. For multiple comparisons the Bonferroni correction will be used. We consider genomic profiling of the affected individuals and identification of new disease-related gene to be a research priority in the field of dystonia, paving the way for future therapeutic studies and putatively serving for the development of preventive strategies in those at risk. Moreover, this study brings novel contribution to the international state of the art by genetically characterizing adult-onset isolated focal dystonia on unrelated affected subjects using the whole-exome sequencing.

Budget: 850.000,00 lei

Host institution: “Carol Davila” University of Medicine and Pharmacy (UMFCD), Department of Neurology at Colentina Teaching Hospital, Bucharest, Romania.

Project leader: Bogdan Ovidiu Popescu, Professor of Neurology and Head of the Neurology Teaching Department at the Colentina Clinical Hospital (Senior Neurologist / Consultant, Research Professor)

Research team:

Research team vacancies: two PhD student positions -> NOW CLOSED

Two doctoral fellows were recruited: Iulia Popescu-Olaru (first year PhD student when recruited; thesis on the relation between certain genetic variants and the response to symptomatic therapy in focal-onset idiopathic dystonia) and Ovidiu-Lucian Băjenaru (first year PhD student when recurited; thesis on the genetics of focal-onset idiopathic dystonia).

What is isolated dystonia?

Dystonia is a group of movement disorders manifesting by sustained or intermittent involuntary contractions of one or several muscles that result in abnormal postures. Depending on the region involved it may be focal (i.e., restricted to a small area – e.g., blepharospasm, torticolis), segmental, multifocal and generalised. It may be caused by a known or identifiable disease, or may appear without any obvious cause. If no structural lesions are found in the brain or the muscles, and the affected person is otherwise healthy, the dystonia is considered primary. In many people with primary focal dystonia there are no obvious accompanying signs or symptoms, thus the name isolated dystonia. The typical onset is in adulthood. For some of these cases a genetic cause has been found (mostly for those with onset during childhood), however most are still without explanation, most likely both genetic predisposition (i.e., gene variants) and environmental factors playing a role in their development.

Why GENDYS?

Isolated focal dystonia is a potentially debilitating movement disorder for which no curative treatments are available. Moreover, state of the art symptomatic treatments are not equally effective for all of the people affected, some of them having only modest improvements. Though dystonia it is thought to be rare, mild focal dystonia cases may be overlooked by medical practitioners without expertise in movement disorders and population-based epidemiological data are scarce, thus its true prevalence, ethnic and geographical distributions as well as phenotypic spectrum and environmental risk factors are incompletely known. A better understanding of the etiology and mechanisms that underlay the development of isolated focal dystonia is required for the future development of effective disease modifying therapies.

The etiology of isolated focal dystonia is undoubtedly genetic in some, but over 75% of the cases are still classified as idiopathic (i.e., without a known cause). In most of these idiopathic cases both genetic and environmental factors are thought to play a role, while in a minority mutations in genes yet unknown to be related to dystonia may be the cause. Whole exome sequencing (WES) using the Next Generation Sequencing (NGS) technique is increasingly employed to find rare disease-causing alleles and was successful in identifying some of the currently known dystonia-related genes. GENDYS uses targeted NGS and WES aiming to identifying new pathogenic gene variants and putative genes yet unknown to be related to this type of disorders. GENDYS will also provide a detailed clinical and genetic description of a moderate-size group of Romanian patients with isolated focal dystonia.

OBJECTIVES OF THE PROJECT:

  1. To describe potential correlations between genetic variants and the clinical profile in a group of Romanian patients with adult-onset focal isolated dystonia, by targeted sequencing the currently known adult-onset focal isolated dystonia-related genes.
  2. To identify potentially new genetic variants related to adult-onset focal isolated dystonia, by evaluating the sub-group of patients negative for currently known focal isolated dystonia-related gene variants, using a Next Generation whole exome sequencing approach.

EXPECTED RESULTS:

  1. a detailed, moderate-size, adult-onset focal isolated dystonia data base (clinical and genetic features for 120 cases), and the corresponding biobank-stored biological samples.
  2. a personalized screening panel for identifying possible variants of the genes currently known to be related to adult-onset focal isolated dystonia.
  3. the scientific report regarding possible correlations between the genomic profile and the phenotype of the patients in respect to the currently known focal isolated dystonia-related genes
  4. the scientific report regarding the potentially new focal onset dystonia-related genes and gene variants found by whole-exome sequencing.

CURRENT STATUS:  ongoing (end date: the 31st of December 2019)

  • patient recruitment is closed
  • the clinical evaluation of the patients and the genetic screening are finished

September 2017: GENDYS received the approval of the local Research Ethics Committee.

December 2017: An original gene panel was designed and build to screen for variants in 30 nuclear genes known or thought to be relevant for dystonia (i.e., the GENDYS panel).

September 2017 – September 2019:

  • 120 Romanian patients with adult-onset isolated focal dystonia were enrolled: 57 with cervical dystonia, 53 with blepharospasm and 10 with other phenotypes; mean disease duration 8 years.
  • the 120 patients and 97 controls were screened using the GENDYS panel (PCR for gene amplification, NGS for variants/mutations identification, Sanger sequencing for variants/mutations confirmation); as a result 87 potentially pathogenic variants were identified in 10 different genes, most located on chromosomes 9 and 11; 96 out of the 120 patients have at least 1 of these variants.
  • WES of samples from dystonia patients without potentially pathogenic variants identified by the GENDYS panel screening is ongoing.

International scientific communications and publications:

Academic communications:

  • Popescu-Olaru: Phenotypes and demographic characteristics in a group of Romanian patients with focal idiopathic dystonia - 2nd year PhD Report
  • OL. Băjenaru: Motor and non-motor clinical findings in people with various phenotypes of idiopathic focal-onset dystonia - 2nd year PhD Report
  • E. Șerban: licence dissertation held at UMFCD Medical School, Department of Clinical Neurosciences, Discipline of Neurology, Colentina Teaching Hospital – ”Correlations between phenotype and environmental factors in a group of patients with focal-onset isolated dystonia treated with botulinum toxin”, scientific supervisor L. Dumitrescu, scientific coordinator Prof. B.O. Popescu.

Romanian associations for people with dystonia: https://distonianational.ro

For more information please contact us: Tel. no. +40213173245, int. 5320 - Neurology Department, Colentina Teaching Hospital, Ștefan cel Mare 19-21, 020125, Bucharest, Romania;

E-mail: cercetare@umfcd.ro

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