title: LoFtool: a gene intolerance score based on loss-of-function variants in 60 706 individuals.
abstract: Depletion of loss-of-function (LoF) mutations may provide a rank of genic functional intolerance and consequently susceptibility to disease.
  
  
  
  Here we have studied LoF mutations in 60 706 unrelated individuals and show that the most intolerant quartile of ranked genes is enriched in rare and early onset diseases and explains 87% of de novo haploinsufficient OMIM mutations, 17% more than any other gene scoring tool. We detected particular enrichment in expression of the depleted LoF genes in brain (odds ratio = 1.5; P -value = 4.2e-07). By searching for de novo haploinsufficient mutations putatively associated with neurodevelopmental disorders in four recent studies, we were able to explain 81% of them. Taken together, this study provides a novel gene intolerance ranking system, called LoFtool, which may help in ranking genes of interest based on their LoF intolerance and tissue expression.
  
  
  
  The LoFtool gene scores are available in the Supplementary data .
  
  
  
  joaofadista@gmail.com.
  
  
  
  Supplementary data are available at Bioinformatics online.
authors: Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen S, Denmark.|Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Sweden and.
authors: João
authors: J
authors: Fadista
authors: Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Sweden and.
authors: Nikolay
authors: N
authors: Oskolkov
authors: Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Sweden and.
authors: Ola
authors: O
authors: Hansson
authors: Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Sweden and.|Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors: Leif
authors: L
authors: Groop
mesh_terms: D001921:Brain; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D000073658:Loss of Function Mutation; D012984:Software