title: Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive degeneration of motor neurons, ultimately leading to paralysis and death. Approximately 10% of ALS cases are familial, with the remaining 90% of cases being sporadic. Genetic studies in familial cases of ALS have been extremely informative in determining the causative mutations behind ALS, especially as the same mutations identified in familial ALS can also cause sporadic disease. However, the cause of ALS in approximately 30% of familial cases and in the majority of sporadic cases remains unknown. Sporadic ALS cases represent an underutilized resource for genetic information about ALS; therefore, we undertook a targeted sequencing approach of 169 known and candidate ALS disease genes in 242 sporadic ALS cases and 129 matched controls to try to identify novel variants linked to ALS. We found a significant enrichment in novel and rare variants in cases versus controls, indicating that we are likely identifying disease associated mutations. This study highlights the utility of next generation sequencing techniques combined with functional studies and rare variant analysis tools to provide insight into the genetic etiology of a heterogeneous sporadic disease.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Julien
authors.initials: J
authors.lastname: Couthouis
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Alya R
authors.initials: AR
authors.lastname: Raphael
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Roxana
authors.initials: R
authors.lastname: Daneshjou
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D000073885:C9orf72 Protein; D016022:Case-Control Studies; D004265:DNA Helicases; D005091:Exons; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D064251:Multifunctional Enzymes; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D020365:RNA Helicases / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000235:genetics
chemical_list: C438187:ALS2 protein, human; D001057:Apolipoproteins E; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C000599550:FUS protein, human; D020662:Guanine Nucleotide Exchange Factors; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D064251:Multifunctional Enzymes; D011506:Proteins; D034702:RNA-Binding Protein FUS; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases