Evaluating the contribution of the gene TARDBP in Italian patients with amyotrophic lateral sclerosis
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Le résumé fourni par la source
BACKGROUND AND OBJECTIVES: Genetic variants in the gene TARDBP, encoding TDP-43 protein, are associated with amyotrophic lateral sclerosis (ALS) in familial (fALS) and sporadic (sALS) cases. Objectives of this study were to assess the contribution of TARDBP in a large cohort of Italian ALS patients, to determine the TARDBP-associated clinical features and to look for genotype-phenotype correlation and penetrance of the mutations. METHODS: A total of 1992 Italian ALS patients (193 fALS and 1799 sALS) were enrolled in this study. Sanger sequencing of TARDBP gene was performed in patients and, when available, in patients' relatives. RESULTS: In total, 13 different rare variants were identified in 43 index cases (10 fALS and 33 sALS) with a cumulative mutational frequency of 2.2% (5.2% of fALS, 1.8% of sALS). The most prevalent variant was the p.A382T followed by the p.G294V. Cognitive impairment was detected in almost 30% of patients. While some variants, including the p.G294V and the p.G376D, were associated with restricted phenotypes, the p.A382T showed a marked clinical heterogeneity regarding age of onset, survival and association with cognitive impairment. Investigations in parents, when possible, showed that the variants were inherited from healthy carriers and never occurred de novo. CONCLUSIONS: In our cohort, TARDBP variants have a relevant frequency in Italian ALS patients and they are significantly associated with cognitive impairment. Clinical presentation is heterogeneous. Consistent genotype-phenotype correlations are limited to some mutations. A marked phenotypic variability characterizes the p.A382T variant, suggesting a multifactorial/oligogenic pathogenic mechanism.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Evaluating the contribution of the gene TARDBP in Italian patients with amyotrophic lateral sclerosis
- Date Crossref
- 23/02/2023
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Università Cattolica del Sacro Cuore Department of Neuroscience pays non établi dans la noticeUniversité ou école supérieure
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Agostino Gemelli University Polyclinic pays non établi dans la noticeÉtablissement de santé
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Istituti di Ricovero e Cura a Carattere Scientifico pays non établi dans la noticeÉtablissement de santé
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Centro Clinico Nemo pays non établi dans la noticeÉtablissement de santé
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Section of Genomic Medicine pays non établi dans la noticeInstitution
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Department of Laboratory and Infectious Disease Sciences Fondazione Policlinico Universitario A. Gemelli IRCCS Rome Italy Unit of Medical Genetics pays non établi dans la noticeStructure de recherche
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Adult NEMO Clinical Center pays non établi dans la noticeÉtablissement de santé
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Research & pays non établi dans la noticeInstitution
Department of Neuroscience — Università Cattolica del Sacro Cuore, Agostino Gemelli University Polyclinic et Istituti di Ricovero e Cura a Carattere Scientifico, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.