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

Yuval Itan, Lei Shang, Bertrand Boisson, Etienne Patin, Alexandre Bolze, Marcela Moncada-Vélez, Eric Scott, Michael J. Ciancanelli, Fabien G. Lafaille, Janet G. Markle, Ruben Martinez-Barricarte, Sarah Jill De Jong, Xiao Fei Kong, Patrick Nitschke, Aziz Belkadi, Jacinta Bustamante, Anne Puel, Stéphanie Boisson-Dupuis, Peter D. Stenson, Joseph G. GleesonDavid N. Cooper, Lluis Quintana-Murci, Jean Michel Claverie, Shen Ying Zhang, Laurent Abel, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)13615-13620
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - Nov 3 2015
Externally publishedYes


  • Gene prioritization
  • Gene-level
  • Mutational damage
  • Next generation sequencing
  • Variant prioritization

ASJC Scopus subject areas

  • General


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