title: Resequencing of 29 candidate genes in patients with familial and sporadic amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  To identify novel disease-causing genes for amyotrophic lateral sclerosis (ALS).
  
  
  METHODS
  We carried out a systematic mutation screening of the entire coding regions of 29 candidate genes encoding critically important proteins for proper differentiation and development of corticospinal motor neurons in 190 patients with familial and sporadic ALS.
  
  
  METHODS
  We focused our analysis on coding variants and evaluated the distribution of nonsynonymous and synonymous variants in our cohort of patients with ALS.
  
  
  RESULTS
  We identified 40 novel nonsynonymous variants and showed a significant excess of unique nonsynonymous variants in our cohort of patients with ALS, which suggests the presence of ALS-predisposing mutations.
  
  
  CONCLUSIONS
  Using a multifaceted approach based on the functional prediction of missense variants, the conservation of the altered amino acid, and the cosegregation of the variants identified in familial cases, we identified several promising novel genes for ALS such as LUM and CRYM. We have also highlighted the analytical challenges of large-scale sequencing screens to detect disease-causing variants.
authors.affiliation: Centre of Excellence in Neuromics, Centre hospitalier de l'Université de Montréal Research Center, 2099 Alexandre De-Seve St., Montreal, QC, Canada.
authors.forename: Hussein
authors.initials: H
authors.lastname: Daoud
authors.forename: Paul N
authors.initials: PN
authors.lastname: Valdmanis
authors.forename: Francois
authors.initials: F
authors.lastname: Gros-Louis
authors.forename: Véronique
authors.initials: V
authors.lastname: Belzil
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Edouard
authors.initials: E
authors.lastname: Henrion
authors.forename: Ousmane
authors.initials: O
authors.lastname: Diallo
authors.forename: Anne
authors.initials: A
authors.lastname: Desjarlais
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.forename: William
authors.initials: W
authors.lastname: Camu
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics; D003459:Crystallins / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007632:Keratan Sulfate / Q000235:genetics; D000071234:Lumican; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons; D020125:Mutation, Missense; D011712:Pyramidal Tracts; D000090803:mu-Crystallins
chemical_list: C000716469:CRYM protein, human; D011508:Chondroitin Sulfate Proteoglycans; D003459:Crystallins; C000604306:LUM protein, human; D000071234:Lumican; D007632:Keratan Sulfate; D000090803:mu-Crystallins