title: Genetic architecture of ALS in Sardinia.
abstract: Conserved populations, such as Sardinians, displaying elevated rates of familial or sporadic amyotrophic lateral sclerosis (ALS) provide unique information on the genetics of the disease. Our aim was to describe the genetic profile of a consecutive series of ALS patients of Sardinian ancestry. All ALS patients of Sardinian ancestry, identified between 2008 and 2013 through the Italian ALS Genetic Consortium, were eligible to be included in the study. Patients and controls underwent the analysis of TARDBP, C9ORF72, SOD1, and FUS genes. Genetic mutations were identified in 155 out of 375 Sardinian ALS cases (41.3%), more commonly the p.A382T and p.G295S mutations of TARDBP and the GGGGCC hexanucleotide repeat expansion of C9ORF72. One patient had both p.G295S and p.A382T mutations of TARDBP and 8 carried both the heterozygous p.A382T mutation of TARDBP and a repeat expansion of C9ORF72. Patients carrying the p.A382T and the p.G295S mutations of TARDBP and the C9ORF72 repeat expansion shared distinct haplotypes across these loci. Patients with cooccurrence of C9ORF72 and TARDBP p.A382T missense mutation had a significantly lower age at onset and shorter survival. More than 40% of all cases on the island of Sardinia carry a mutation of an ALS-related gene, representing the highest percentage of ALS cases genetically explained outside of Scandinavia. Clinical phenotypes associated with different genetic mutations show some distinctive characteristics, but the heterogeneity between and among families carrying the same mutations implies that ALS manifestation is influenced by other genetic and nongenetic factors.
authors.affiliation: Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borghero
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Pugliatti
authors.affiliation: Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marrosu
authors.affiliation: Multiple Sclerosis Center Laboratory, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Marrosu
authors.affiliation: Multiple Sclerosis Center Laboratory, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Murru
authors.affiliation: Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Floris
authors.affiliation: Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Cannas
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Leslie D
authors.initials: LD
authors.lastname: Parish
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Occhineri
authors.affiliation: Azienda Sanitaria Locale n. 2, Olbia-Tempio, Italy.
authors.forename: Tea B
authors.initials: TB
authors.lastname: Cau
authors.affiliation: Azienda Sanitaria Locale n. 2, Olbia-Tempio, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Loi
authors.affiliation: Department of Neurology, Azienda Ospedaliera San Francesco, Nuoro, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ticca
authors.affiliation: Department of Neurology, Ospedale Antonio Segni, Ozieri, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Traccis
authors.affiliation: Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Manera
authors.affiliation: Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genoa, Genoa, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Canosa
authors.affiliation: Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Moglia
authors.affiliation: Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.affiliation: Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Barberis
authors.affiliation: Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Brunetti
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA.
authors.forename: Hannah A
authors.initials: HA
authors.lastname: Pliner
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Renton
authors.affiliation: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA; Department of Neurology, Brain Science Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.affiliation: Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Restagno
authors.affiliation: Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genoa, Genoa, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy; Neuroscience Institute of Torino (NIT), Turin, Italy. Electronic address: achio@usa.net.
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
mesh_terms: D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007558:Italy / Q000453:epidemiology; D009154:Mutation; D019683:Penetrance; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D011506:Proteins; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; C000598624:TARDBP protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Genetics; Penetrance; Phenotype; Prognosis; Sardinia