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Am J Hum Genet. 2015 Jun 4;96(6):913-25. doi: 10.1016/j.ajhg.2015.04.013.

Individualized iterative phenotyping for genome-wide analysis of loss-of-function mutations.

Author information

1
National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
2
National Institute for Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
3
National Eye Institute, NIH, Bethesda, MD 20892, USA.
4
National Cancer Institute, NIH, Bethesda, MD 20892, USA.
5
National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
6
Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
7
National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; NIH Intramural Sequencing Center, NIH, Bethesda, MD 20892, USA.
8
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.

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.

PMID:
26046366
PMCID:
PMC4457956
DOI:
10.1016/j.ajhg.2015.04.013
[Indexed for MEDLINE]
Free PMC Article

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