title: FLAGS, frequently mutated genes in public exomes.
abstract: BACKGROUND
  Dramatic improvements in DNA-sequencing technologies and computational analyses have led to wide use of whole exome sequencing (WES) to identify the genetic basis of Mendelian disorders. More than 180 novel rare-disease-causing genes with Mendelian inheritance patterns have been discovered through sequencing the exomes of just a few unrelated individuals or family members. As rare/novel genetic variants continue to be uncovered, there is a major challenge in distinguishing true pathogenic variants from rare benign mutations.
  
  
  METHODS
  We used publicly available exome cohorts, together with the dbSNP database, to derive a list of genes (n = 100) that most frequently exhibit rare (<1%) non-synonymous/splice-site variants in general populations. We termed these genes FLAGS for FrequentLy mutAted GeneS and analyzed their properties.
  
  
  RESULTS
  Analysis of FLAGS revealed that these genes have significantly longer protein coding sequences, a greater number of paralogs and display less evolutionarily selective pressure than expected. FLAGS are more frequently reported in PubMed clinical literature and more frequently associated with diseased phenotypes compared to the set of human protein-coding genes. We demonstrated an overlap between FLAGS and the rare-disease causing genes recently discovered through WES studies (n = 10) and the need for replication studies and rigorous statistical and biological analyses when associating FLAGS to rare disease. Finally, we showed how FLAGS are applied in disease-causing variant prioritization approach on exome data from a family affected by an unknown rare genetic disorder.
  
  
  CONCLUSIONS
  We showed that some genes are frequently affected by rare, likely functional variants in general population, and are frequently observed in WES studies analyzing diverse rare phenotypes. We found that the rate at which genes accumulate rare mutations is beneficial information for prioritizing candidates. We provided a ranking system based on the mutation accumulation rates for prioritizing exome-captured human genes, and propose that clinical reports associating any disease/phenotype to FLAGS be evaluated with extra caution.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Vancouver, BC, Canada. casper@cmmt.ubc.ca.|Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. casper@cmmt.ubc.ca.|Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada. casper@cmmt.ubc.ca.
authors.forename: Casper
authors.initials: C
authors.lastname: Shyr
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Vancouver, BC, Canada. maja@cmmt.ubc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. maja@cmmt.ubc.ca.|Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. maja@cmmt.ubc.ca.
authors.forename: Maja
authors.initials: M
authors.lastname: Tarailo-Graovac
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Vancouver, BC, Canada. mike.m.gottlieb@gmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Gottlieb
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Vancouver, BC, Canada. leejae7@interchange.ubc.ca.|Genome Science and Technology Graduate Program, University of British Columbia, Vancouver, BC, Canada. leejae7@interchange.ubc.ca.
authors.forename: Jessica J Y
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. cvankarnebeek@cw.bc.ca.|Division of Biochemical Diseases, BC Children's Hospital, Vancouver, BC, Canada. cvankarnebeek@cw.bc.ca.|Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. cvankarnebeek@cw.bc.ca.
authors.forename: Clara
authors.initials: C
authors.lastname: van Karnebeek
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Vancouver, BC, Canada. wyeth@cmmt.ubc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. wyeth@cmmt.ubc.ca.|Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. wyeth@cmmt.ubc.ca.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D002675:Child, Preschool; D016208:Databases, Factual; D066264:Datasets as Topic; D059472:Exome / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D006801:Humans; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D017423:Sequence Analysis, RNA / Q000379:methods*
chemical_list: D015415:Biomarkers