title: SOD1, ANG, TARDBP and FUS mutations in amyotrophic lateral sclerosis: a United States clinical testing lab experience.
abstract: SOD1, ANG, TARDBP and FUS mutations have been associated with amyotrophic lateral sclerosis (ALS). Our goal was to extend molecular genetic analysis to newly identified ALS genetic loci and to determine the frequency of mutations, distribution of disease genes, and variant spectrum of these genes in a large United States ALS-phenotype cohort. We screened 1220 probands with an ALS phenotype, referred originally for SOD1 molecular genetic analysis. 1128 SOD1-negative probands were screened for ANG, and 277 and 223 SOD1- and ANG-negative samples were screened for TARDBP and FUS, respectively. One hundred additional probands were specifically screened only for FUS exon 15. We identified a total of 36 different SOD1 mutations, including three novel mutations, in 92 probands. ANG screening identified three mutations, including two novel mutations, and TARDBP screening identified two previously reported TARDBP mutations. We also identified four mutations in FUS, including the reported FUS in-frame deletion, c.430_447del, p.Gly144_Tyr149del, in a patient with inclusion body myositis, and two known FUS missense mutations. From this study, we estimate frequencies for SOD1, ANG, TARDBP and FUS mutations, in this United States cohort, to be 7.5%, 0.71%, 0.72% and 1.9%, respectively. In conclusion, we identify novel variants in SOD1, ANG, TARDBP and FUS, and expand the FUS-associated clinicopathologic phenotype.
authors.affiliation: Neurogenetics DNA Diagnostic Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Brown
authors.forename: Jionghong
authors.initials: J
authors.lastname: Min
authors.forename: John F
authors.initials: JF
authors.lastname: Staropoli
authors.forename: Elisa
authors.initials: E
authors.lastname: Collin
authors.forename: Stephen
authors.initials: S
authors.lastname: Bi
authors.forename: Xin
authors.initials: X
authors.lastname: Feng
authors.forename: Rosemary
authors.initials: R
authors.lastname: Barone
authors.forename: Yi
authors.initials: Y
authors.lastname: Cao
authors.forename: Lei
authors.initials: L
authors.lastname: O'Malley
authors.forename: Winnie
authors.initials: W
authors.lastname: Xin
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mullen
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Sims
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000503:physiopathology; D019411:Clinical Laboratory Techniques; D004268:DNA-Binding Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D009154:Mutation; D010641:Phenotype; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D012259:Ribonuclease, Pancreatic / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D014481:United States
chemical_list: D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C046366:angiogenin; D012259:Ribonuclease, Pancreatic