A systematic approach to mapping recessive disease genes in individuals from outbred populations

Friedhelm Hildebrandt, Saskia F. Heeringa, Franz Rüschendorf, Massimo Attanasio, Gudrun Nürnberg, Christian Becker, Dominik Seelow, Norbert Huebner, Gil Chernin, Christopher N. Vlangos, Weibin Zhou, John F. O'Toole, Bethan E. Hoskins, Matthias T F Wolf, Bernward G. Hinkes, Hassan Chaib, Shazia Ashraf, Susan J. Allen, Virginia Vega-Warner, Eric WiseHeather M. Harville, Robert H. Lyons, Joseph Washburn, James MacDonald, Peter Nürnberg, Edgar A. Otto

Research output: Contribution to journalArticlepeer-review

136 Scopus citations


The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes.

Original languageEnglish (US)
Article numbere1000353
JournalPLoS genetics
Issue number1
StatePublished - Jan 2009

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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