title: Secondary findings and carrier test frequencies in a large multiethnic sample.
abstract: BACKGROUND
  Besides its growing importance in clinical diagnostics and understanding the genetic basis of Mendelian and complex diseases, whole exome sequencing (WES) is a rich source of additional information of potential clinical utility for physicians, patients and their families. We analyzed the frequency and nature of single nucleotide variants (SNVs) considered secondary findings and recessive disease allele carrier status in the exomes of 8554 individuals from a large, randomly sampled cohort study and 2514 patients from a study of presumed Mendelian disease having undergone WES.
  
  
  METHODS
  We used the same sequencing platform and data processing pipeline to analyze all samples and characterized the distributions of reported pathogenic (ClinVar, Human Gene Mutation Database (HGMD)) and predicted deleterious variants in the pre-specified American College of Medical Genetics and Genomics (ACMG) secondary findings and recessive disease genes in different ethnic groups.
  
  
  RESULTS
  In the 56 ACMG secondary findings genes, the average number of predicted deleterious variants per individual was 0.74, and the mean number of ClinVar reported pathogenic variants was 0.06. We observed an average of 10 deleterious and 0.78 ClinVar reported pathogenic variants per individual in 1423 autosomal recessive disease genes. By repeatedly sampling pairs of exomes, 0.5 % of the randomly generated couples were at 25 % risk of having an affected offspring for an autosomal recessive disorder based on the ClinVar variants.
  
  
  CONCLUSIONS
  By investigating reported pathogenic and novel, predicted deleterious variants we estimated the lower and upper limits of the population fraction for which exome sequencing may reveal additional medically relevant information. We suggest that the observed wide range for the lower and upper limits of these frequency numbers will be gradually reduced due to improvement in classification databases and prediction algorithms.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 USA ; Institute of Computer Science, Warsaw University of Technology, Warsaw, 00-665 Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030 USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030 USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Below
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.affiliation: The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030 USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030 USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Staples
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030 USA.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030 USA.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Bainbridge
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030 USA ; Texas Children's Hospital, Houston, TX 77030 USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Penney
authors.affiliation: The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030 USA ; Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, TX 77030 USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: McGuire
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 USA ; The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030 USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 USA ; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030 USA ; Texas Children's Hospital, Houston, TX 77030 USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030 USA ; Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030 USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle