Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations

被引：53

作者：

Johnston, Jennifer J. ^{[1
]}

Lewis, Katie L. ^{[1
]}

Ng, David ^{[1
]}

Singh, Larry N. ^{[1
]}

Wynter, Jamila ^{[1
]}

Brewer, Carmen ^{[2
]}

Brooks, Brian P. ^{[3
]}

Brownell, Isaac ^{[4
]}

Candotti, Fabio ^{[1
]}

Gonsalves, Steven G. ^{[1
]}

Hart, Suzanne P. ^{[1
]}

Kong, Heidi H. ^{[4
]}

Rother, Kristina I. ^{[5
]}

Sokolic, Robert ^{[1
]}

Solomon, Benjamin D. ^{[1
]}

Zein, Wadih M. ^{[3
]}

Cooper, David N. ^{[6
]}

Stenson, Peter D. ^{[6
]}

Mullikin, James C. ^{[1
,7
]}

Biesecker, Leslie G. ^{[1
,7
]}

机构：

[1] NHGRI, NIH, Bethesda, MD 20892 USA

[2] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA

[3] NEI, NIH, Bethesda, MD 20892 USA

[4] NCI, NIH, Bethesda, MD 20892 USA

[5] NIDDK, NIH, Bethesda, MD 20892 USA

[6] Cardiff Univ, Inst Med Genet, Sch Med, Cardiff CF14 4XN, S Glam, Wales

[7] NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2015年 / 96卷 / 06期

关键词：

DISEASE; PROTEIN; VARIANTS;

D O I：

10.1016/j.ajhg.2015.04.013

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：913 / 925

页数：13