title: Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk.
abstract: OBJECTIVE
  Carrier screening for mutations contributing to cystic fibrosis (CF) is typically accomplished with panels composed of variants that are clinically validated primarily in patients of European descent. This approach has created a static genetic and phenotypic profile for CF. An opportunity now exists to reevaluate the disease profile of CFTR at a global population level.
  
  
  METHODS
  CFTR allele and genotype frequencies were obtained from a nonpatient cohort with more than 60,000 unrelated personal genomes collected by the Exome Aggregation Consortium. Likely disease-contributing mutations were identified with the use of public database annotations and computational tools.
  
  
  RESULTS
  We identified 131 previously described and likely pathogenic variants and another 210 untested variants with a high probability of causing protein damage. None of the current genetic screening panels or existing CFTR mutation databases covered a majority of deleterious variants in any geographical population outside of Europe.
  
  
  CONCLUSIONS
  Both clinical annotation and mutation coverage by commercially available targeted screening panels for CF are strongly biased toward detection of reproductive risk in persons of European descent. South and East Asian populations are severely underrepresented, in part because of a definition of disease that preferences the phenotype associated with European-typical CFTR alleles.
authors.affiliation: GenePeeks, Inc., New York, New York, USA.
authors.forename: Regine M
authors.identifier: http://orcid.org/0000-0002-2306-4192
authors.initials: RM
authors.lastname: Lim
authors.affiliation: GenePeeks, Inc., New York, New York, USA.|GenePeeks, Inc., Cambridge, Massachusetts, USA.
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Silver
authors.affiliation: GenePeeks, Inc., New York, New York, USA.
authors.forename: Maxwell J
authors.identifier: http://orcid.org/0000-0002-1748-9004
authors.initials: MJ
authors.lastname: Silver
authors.affiliation: GenePeeks, Inc., New York, New York, USA.
authors.forename: Carlos
authors.identifier: http://orcid.org/0000-0002-3994-8283
authors.initials: C
authors.lastname: Borroto
authors.affiliation: GenePeeks, Inc., New York, New York, USA.
authors.forename: Brett
authors.identifier: http://orcid.org/0000-0003-4522-5847
authors.initials: B
authors.lastname: Spurrier
authors.affiliation: GenePeeks, Inc., New York, New York, USA.
authors.forename: Tanya C
authors.initials: TC
authors.lastname: Petrossian
authors.affiliation: GenePeeks, Inc., Cambridge, Massachusetts, USA.
authors.forename: Jessica L
authors.identifier: http://orcid.org/0000-0003-2619-3579
authors.initials: JL
authors.lastname: Larson
authors.affiliation: GenePeeks, Inc., New York, New York, USA.|GenePeeks, Inc., Cambridge, Massachusetts, USA.|Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.|Woodrow Wilson School of Public and International Affairs, Princeton University, Princeton, New Jersey, USA.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Silver
mesh_terms: D003550:Cystic Fibrosis / Q000175:diagnosis* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D006580:Genetic Carrier Screening; D005820:Genetic Testing; D006801:Humans; D008403:Mass Screening; D009154:Mutation; D012307:Risk Factors
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator