title: Individualized iterative phenotyping for genome-wide analysis of loss-of-function mutations.
abstract: Next-generation sequencing provides the opportunity to practice predictive medicine based on identified variants. Putative loss-of-function (pLOF) variants are common in genomes and understanding their contribution to disease is critical for predictive medicine. To this end, we characterized the consequences of pLOF variants in an exome cohort by iterative phenotyping. Exome data were generated on 951 participants from the ClinSeq cohort and filtered for pLOF variants in genes likely to cause a phenotype in heterozygotes. 103 of 951 exomes had such a pLOF variant and 79 participants were evaluated. Of those 79, 34 had findings or family histories that could be attributed to the variant (28 variants in 18 genes), 2 had indeterminate findings (2 variants in 2 genes), and 43 had no findings or a negative family history for the trait (34 variants in 28 genes). The presence of a phenotype was correlated with two mutation attributes: prior report of pathogenicity for the variant (p = 0.0001) and prior report of other mutations in the same exon (p = 0.0001). We conclude that 1/30 unselected individuals harbor a pLOF mutation associated with a phenotype either in themselves or their family. This is more common than has been assumed and has implications for the setting of prior probabilities of affection status for predictive medicine.
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Johnston
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Lewis
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ng
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Larry N
authors.initials: LN
authors.lastname: Singh
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Jamila
authors.initials: J
authors.lastname: Wynter
authors.affiliation: National Institute for Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Brewer
authors.affiliation: National Eye Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Brooks
authors.affiliation: National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Brownell
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Gonsalves
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Suzanne P
authors.initials: SP
authors.lastname: Hart
authors.affiliation: National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Heidi H
authors.initials: HH
authors.lastname: Kong
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Kristina I
authors.initials: KI
authors.lastname: Rother
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Sokolic
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Solomon
authors.affiliation: National Eye Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Wadih M
authors.initials: WM
authors.lastname: Zein
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Stenson
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; NIH Intramural Sequencing Center, NIH, Bethesda, MD 20892, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; NIH Intramural Sequencing Center, NIH, Bethesda, MD 20892, USA. Electronic address: lesb@mail.nih.gov.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
mesh_terms: D050197:Atherosclerosis / Q000235:genetics*; D019295:Computational Biology; D059472:Exome / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods* / Q000639:trends; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D057285:Precision Medicine / Q000379:methods*