VARPRISM

VARPRISM integrates functional variant prioritization with gene-level likelihood ratio testing to detect and prioritize de novo exonic mutations that influence disease risk.

Key Features:

• Functional Variant Prioritization: Evaluates the impact of exonic mutations on protein sequences and estimates whether variants are likely benign or damaging.
• Gene-level Likelihood Ratio Testing: Conducts likelihood ratio tests at the gene level to assess the association between de novo mutations and disease risk.
• Integration to Increase Statistical Power: Incorporates functional predictions into association testing to increase the statistical power to detect disease-influencing mutations.
• Application to Simons Simplex Collection: Applied to 2,508 parent-offspring autism trios from the Simons Simplex Collection, replicating findings for 44 previously implicated autism genes and identifying 20 additional candidate genes at false discovery rate < 0.3.
• Identification of Novel Candidate Genes: Reported novel candidate genes including MYO1E, KCND3, PDCD1, DLX3, and TSPAN4.

Scientific Applications:

• Autism spectrum disorder: Enhances detection and prioritization of de novo exonic mutations to pinpoint genes associated with autism risk.
• Complex genetic disease studies: Applicable to studies of complex genetic diseases in which de novo mutations contribute to disease risk.

Methodology:

Assesses functional consequences of exonic mutations on protein sequences and applies gene-level likelihood ratio tests, integrating functional variant prioritization into the statistical association framework.