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LoFtool : a gene intolerance score based on loss-of-function variants in 60 706 individuals

  • João Fadista
  • Nikolay Oskolkov
  • Ola Hansson
  • Leif Groop
Publiceringsår: 2017
Språk: Engelska
Sidor: 471-474
Publikation/Tidskrift/Serie: Bioinformatics
Volym: 33
Nummer: 4
Dokumenttyp: Artikel i tidskrift
Förlag: Oxford University Press

Abstract english

MOTIVATION: Depletion of loss-of-function (LoF) mutations may provide a rank of genic functional intolerance and consequently susceptibility to disease.

RESULTS: Here we have studied LoF mutations in 60 706 unrelated individuals and show that the most intolerant quartile of ranked genes is enriched in rare and early onset diseases and explains 87% of de novo haploinsufficient OMIM mutations, 17% more than any other gene scoring tool. We detected particular enrichment in expression of the depleted LoF genes in brain (odds ratio = 1.5; P-value = 4.2e-07). By searching for de novo haploinsufficient mutations putatively associated with neurodevelopmental disorders in four recent studies, we were able to explain 81% of them. Taken together, this study provides a novel gene intolerance ranking system, called LoFtool, which may help in ranking genes of interest based on their LoF intolerance and tissue expression.

AVAILABILITY AND IMPLEMENTATION: The LoFtool gene scores are available in the Supplementary data CONTACT: joaofadista [at] gmail [dot] comSupplementary information: Supplementary data are available at Bioinformatics online.


  • Medical Genetics


  • Genomics, Diabetes and Endocrinology
  • ISSN: 1367-4803
Nikolay Oskolkov
E-post: nikolay [dot] oskolkov [at] biol [dot] lu [dot] se


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