title: C9ORF72 repeat expansion in a large Italian ALS cohort: evidence of a founder effect.
abstract: A hexanucleotide repeat expansion (RE) in C9ORF72 gene was recently reported as the main cause of amyotrophic lateral sclerosis (ALS) and cases with frontotemporal dementia. We screened C9ORF72 in a large cohort of 259 familial ALS, 1275 sporadic ALS, and 862 control individuals of Italian descent. We found RE in 23.9% familial ALS, 5.1% sporadic ALS, and 0.2% controls. Two cases carried the RE together with mutations in other ALS-associated genes. The phenotype of RE carriers was characterized by bulbar-onset, shorter survival, and association with cognitive and behavioral impairment. Extrapyramidal and cerebellar signs were also observed in few patients. Genotype data revealed that 95% of RE carriers shared a restricted 10-single nucleotide polymorphism haplotype within the previously reported 20-single nucleotide polymorphism risk haplotype, detectable in only 27% of nonexpanded ALS cases and in 28% of controls, suggesting a common founder with cohorts of North European ancestry. Although C9ORF72 RE segregates with disease, the identification of RE both in controls and in patients carrying additional pathogenic mutations suggests that penetrance and phenotypic expression of C9ORF72 RE may depend on additional genetic risk factors.
authors: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy. antonia.ratti@unimi.it
authors: Antonia
authors: A
authors: Ratti
authors: Lucia
authors: L
authors: Corrado
authors: Barbara
authors: B
authors: Castellotti
authors: Roberto
authors: R
authors: Del Bo
authors: Isabella
authors: I
authors: Fogh
authors: Cristina
authors: C
authors: Cereda
authors: Cinzia
authors: C
authors: Tiloca
authors: Carla
authors: C
authors: D'Ascenzo
authors: Alessandra
authors: A
authors: Bagarotti
authors: Viviana
authors: V
authors: Pensato
authors: Michela
authors: M
authors: Ranieri
authors: Stella
authors: S
authors: Gagliardi
authors: Daniela
authors: D
authors: Calini
authors: Letizia
authors: L
authors: Mazzini
authors: Franco
authors: F
authors: Taroni
authors: Stefania
authors: S
authors: Corti
authors: Mauro
authors: M
authors: Ceroni
authors: Gaia D
authors: GD
authors: Oggioni
authors: Kuang
authors: K
authors: Lin
authors: John F
authors: JF
authors: Powell
authors: Gianni
authors: G
authors: Sorarù
authors: Nicola
authors: N
authors: Ticozzi
authors: Giacomo P
authors: GP
authors: Comi
authors: Sandra
authors: S
authors: D'Alfonso
authors: Cinzia
authors: C
authors: Gellera
authors: Vincenzo
authors: V
authors: Silani
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D001480:Basal Ganglia Diseases / Q000235:genetics; D000073885:C9orf72 Protein; D002526:Cerebellar Diseases / Q000235:genetics; D060825:Cognitive Dysfunction / Q000235:genetics; D015331:Cohort Studies; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012306:Risk; D012737:Sex Factors
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins