ArticleProceedings of the National Academy of Sciences of the United States of America2015
The human gene damage index as a gene-level approach to prioritizing exome variants.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 167 papers, 1 of them a synthesis that pooled it.
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Who cites it
167 citing papers in PubMed, 1 synthesis or guideline pooled it, 277 citations in OpenAlex.
- Meta-analysis of 46,000 germline de novo mutations linked to human inherited disease.Human genomics · 2024Pooled it
- IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.Human genetics · 2021Trial
- The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses.The Journal of experimental medicine · 2018Trial
- Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn's disease.The Journal of clinical investigation · 2018Trial
- Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage.Proceedings of the National Academy of Sciences of the United States of America · 2016Trial
- End-to-end deep learning methods for genetic risk prediction of schizophrenia.Nature communications · 2026Article
- From conservation scores to language models: a feature engineering perspective on machine learning for genetic variant interpretation.Briefings in bioinformatics · 2026Review
- Humans homozygous for rare or common hypomorphic IL23R variants are prone to tuberculosis.The Journal of experimental medicine · 2026Article
- Human inherited RORγT deficiency encompasses genetic heterogeneity, T cell deficiency, and clinical homogeneity.medRxiv : the preprint server for health sciences · 2026Article
- Oncostatin M receptor deficiency as a novel candidate genetic cause of autosomal recessive hyper-IgE syndrome.Journal of human immunity · 2026Article
- Defective RNA Polymerase III sensing of mitochondrial DNA in pulmonary epithelial cells impairs type I IFN immunity to SARS-CoV-2.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Human LFA-1 governs T cell immune surveillance of the skin.Science immunology · 2026Article
- Rare genetic variant risks in patients with sepsis-associated acute respiratory distress syndrome.Respiratory research · 2026Article
- The OAS-RNase L pathway: Insights from experiments of nature.Science immunology · 2026Review
- FAVOR 2.0: A reengineered functional annotation of variants online resource for interpreting genomic variation.Nucleic acids research · 2026Article
- Gene4Denovo2: an updated platform for human de novo mutations discovery and interpretation.Nucleic acids research · 2026Article
- GDIv2: improving variant selection from human exomes.Bioinformatics advances · 2026Article
- Molecular Evolution of the NLR Gene Family Reveals Diverse Innate Immune Strategies in Bats.Biomolecules · 2025Article
- A human YEATS4 variant confers resistance to TST and IGRA conversion despite Mycobacterium tuberculosis exposure.Genome medicine · 2025Article
- Tumor evolution and immune microenvironment dynamics in primary and relapsed mantle cell lymphoma.Cell reports. Medicine · 2025Article
107 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 8 institutions in 4 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.