The human gene damage index as a gene-level approach to prioritizing exome variants

Abstract

The protein-coding exome of a patient with a monogenic disease contains about 20,000 variants, only one or two of which are disease causing. We found that 58% of rare variants in the protein-coding exome of the general population are located in only 2% of the genes. Prompted by this observation, we aimed to develop a gene-level approach for predicting whether a given human protein-coding gene is likely to harbor disease-causing mutations. To this end, we derived the gene damage index (GDI): a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population. We found that the GDI was correlated with selective evolutionary pressure, protein complexity, coding sequence length, and the number of paralogs. We compared GDI with the leading gene-level approaches, genic intolerance, and de novo excess, and demonstrated that GDI performed best for the detection of false positives (i.e., removing exome variants in genes irrelevant to disease), whereas genic intolerance and de novo excess performed better for the detection of true positives (i.e., assessing de novo mutations in genes likely to be disease causing). The GDI server, data, and software are freely available to noncommercial users from lab.rockefeller.edu/casanova/GDI.

Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

“…While applying different genetic model filters with GEMINI, we also filtered variants to remove any where minimum heterozygous allelic balance was less than 0.25 or that had a "High" Gene Damage Index for general Mendelian diseases (http://lab.rockefeller.edu/casanova/GDI; ref. 50).…”

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

“…P3 and P4, one boy and one girl, born to French and German parents, respectively, were aged 5 and 11 years when they developed VZV pneumonitis (P3) and encephalitis (P4 the predicted Mutation Significance Cutoffs (MSC) of 95% confidence (Supplemental Figure 3) (32,33). The genes themselves are highly conserved and subject to purifying selection, with low gene damage index and purification coefficient (34). Immunoblotting of peripheral blood mononuclear cell (PBMC) lysates from P1-P4 for levels of POLR3A and POLR3C revealed that these proteins were expressed at levels comparable to those in healthy controls ( Figure 1C).…”

GAVIN - Gene-Aware Variant INterpretation for medical sequencing

“…For each group, 10,000 sets of 100 benign and 100 pathogenic variants were randomly sampled and tested from the full set of 25,765 variants and accuracy was calculated for gene-specific and genome-wide CADD and MAF thresholds Furthermore, calibration of pathogenic variants could be difficult in genes with high damage tolerance, i.e. having many missense or loss-of-function mutations [26]. In addition, calibration may be impaired by false input signals, such as an incorrect pathogenic classification in ClinVar or inclusion of disease cohorts in large databases such as ExAC could misrepresent allele frequencies [27].…”