title: Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing.
abstract: BACKGROUND
  Over 100 genes have been implicated in the aetiology of amyotrophic lateral sclerosis (ALS). A detailed understanding of their independent and cumulative contributions to disease burden may help guide various clinical and research efforts.
  
  
  METHODS
  Using targeted high-throughput sequencing, we characterised the variation of 10 Mendelian and 23 low penetrance/tentative ALS genes within a population-based cohort of 444 Irish ALS cases (50 fALS, 394 sALS) and 311 age-matched and geographically matched controls.
  
  
  RESULTS
  Known or potential high-penetrance ALS variants were identified within 17.1% of patients (38% of fALS, 14.5% of sALS). 12.8% carried variants of Mendelian disease genes (C9orf72 8.78%; SETX 2.48%; ALS2 1.58%; FUS 0.45%; TARDBP 0.45%; OPTN 0.23%; VCP 0.23%. ANG, SOD1, VAPB 0%), 4.7% carried variants of low penetrance/tentative ALS genes and 9.7% (30% of fALS, 7.1% of sALS) carried previously described ALS variants (C9orf72 8.78%; FUS 0.45%; TARDBP 0.45%). 1.6% of patients carried multiple known/potential disease variants, including all identified carriers of an established ALS variant (p<0.01); TARDBP:c.859G>A(p.[G287S]) (n=2/2 sALS). Comparison of our results with those from studies of other European populations revealed significant differences in the spectrum of disease variation (p=1.7×10(-4)).
  
  
  CONCLUSIONS
  Up to 17% of Irish ALS cases may carry high-penetrance variants within the investigated genes. However, the precise nature of genetic susceptibility differs significantly from that reported within other European populations. Certain variants may not cause disease in isolation and concomitant analysis of disease genes may prove highly important.
authors.affiliation: Smurfit Institute of Genetics, Trinity College, Dublin, Ireland.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Kenna
authors.forename: Russell L
authors.initials: RL
authors.lastname: McLaughlin
authors.forename: Susan
authors.initials: S
authors.lastname: Byrne
authors.forename: Marwa
authors.initials: M
authors.lastname: Elamin
authors.forename: Mark
authors.initials: M
authors.lastname: Heverin
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Kenny
authors.forename: Paul
authors.initials: P
authors.lastname: Cormican
authors.forename: Derek W
authors.initials: DW
authors.lastname: Morris
authors.forename: Colette G
authors.initials: CG
authors.lastname: Donaghy
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bradley
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007494:Ireland; D008297:Male; D008875:Middle Aged; D019683:Penetrance; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D005819:Genetic Markers
keywords: Genetic Epidemiology; Motor Neurone Disease