Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review. (6th December 2020)

• Record Type: Journal Article
• Authors: Gómez‐Garre, Pilar; Jesús, Silvia; Periñán, María Teresa; Adarmes, Astrid; Alonso‐Canovas, Araceli; Blanco‐Ollero, Alberto; Buiza‐Rueda, Dolores; Carrillo, Fátima; Catalán‐Alonso, María José; del Val, Javier; Escamilla‐Sevilla, Francisco; Espinosa‐Rosso, Raúl; Fernández‐Moreno, María Carmen; García‐Moreno, José Manuel; García‐Ruiz, Pedro José; Giacometti‐Silveira, Sandra; Gutiérrez‐García, Javier; López‐Valdés, Eva; Macías‐García, Daniel; Martínez‐Castrillo, Juan Carlos; Martínez‐Torres, Irene; Medialdea‐Natera, María Pilar; Mínguez‐Castellanos, Adolfo; Moya, Miguel Ángel; Ochoa‐Sepulveda, Juan José; Ojea, Tomás; Rodríguez, Nuria; Sillero‐Sánchez, Miriam; Tejera‐Parrado, Cristina; Mir, Pablo
• Is Part Of: European journal of neurology. Volume 28:Number 4(2021)
• Page Start: 1188
• Page End: 1197
• Publication Date: 2020-12-06
• Subjects: isolated dystonia -- TOR1A -- THAP1 -- GNAL -- mutational study -- literature review; Neurology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/ene.14638
• Languages: English
• ISSNs: 1351-5101

Abstract

Abstract: Objective: We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature. Methods: A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high‐resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed. Results: Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A . A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively. Conclusions: There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult‐onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT‐ TOR1A and DYT‐ GNAL, with DYT‐ THAP1 likely to be an intermediate phenotype. Abstract : Although the molecular mechanisms underlying isolated dystonia are largely unknown, it is known that its pathogenesis is genetically heterogeneous. Causative mutations in three genes ( TOR1A, THAP1, and GNAL ) have been identified in patients from different populations. This study is the largest and most complete study of TOR1A, THAP1 and GNAL genes in the Spanish population and a review of the recent genetic findings in these genes. The incidence of pathogenic or likely pathogenic variants in these three genes in our population is low. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT‐ TOR1A and DYT‐ GNAL, with DYT‐ THAP1 likely to be an intermediate phenotype.