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Genome Med. 2016 Aug 25;8(1):91. doi: 10.1186/s13073-016-0341-9.

VARPRISM: incorporating variant prioritization in tests of de novo mutation association.

Author information

1
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
2
Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.
3
Department of Human Genetics and USTAR Center for Genetic Discovery, University of Utah, Salt Lake City, UT, USA.
4
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. chuff1@mdanderson.org.

Abstract

BACKGROUND:

Patients with certain genetic diseases, such as autism spectrum disorder, have increased rates of de novo mutations within some protein-coding genes.

RESULTS:

We introduce the VARiant PRIoritization SuM (VARPRISM), a software package which incorporates functional variant prioritization information to improve the power to detect de novo mutations influencing disease risk. VARPRISM evaluates the consequence of any given exonic mutation on the protein sequence to estimate the likelihood that the mutation is benign or damaging and conducts a likelihood ratio test on the gene level. We analyzed the Simons Simplex Collection of 2508 parent-offspring autism trios using VARPRISM, replicating 44 genes previously implicated in autism susceptibility and identifying 20 additional candidate genes, including MYO1E, KCND3, PDCD1, DLX3, and TSPAN4 (false discovery rate < 0.3).

CONCLUSION:

By incorporating functional predictions, VARPRISM improved the statistical power to identify de novo mutations increasing disease risks. VARPRISM is available at http://www.hufflab.org/software/VARPRISM .

KEYWORDS:

Autism spectrum disorder; De novo mutations; Likelihood ratio test; Simons Simplex Collection; Variant prioritization

PMID:
27562213
PMCID:
PMC4997702
DOI:
10.1186/s13073-016-0341-9
[Indexed for MEDLINE]
Free PMC Article

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