Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review.
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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
Аннотация
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.