title: A systematic approach to mapping recessive disease genes in individuals from outbred populations.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Saskia F
authors.initials: SF
authors.lastname: Heeringa
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Dominik
authors.initials: D
authors.lastname: Seelow
authors.forename: Norbert
authors.initials: N
authors.lastname: Huebner
authors.forename: Gil
authors.initials: G
authors.lastname: Chernin
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Vlangos
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhou
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
authors.forename: Bethan E
authors.initials: BE
authors.lastname: Hoskins
authors.forename: Matthias T F
authors.initials: MT
authors.lastname: Wolf
authors.forename: Bernward G
authors.initials: BG
authors.lastname: Hinkes
authors.forename: Hassan
authors.initials: H
authors.lastname: Chaib
authors.forename: Shazia
authors.initials: S
authors.lastname: Ashraf
authors.forename: Dominik S
authors.initials: DS
authors.lastname: Schoeb
authors.forename: Bugsu
authors.initials: B
authors.lastname: Ovunc
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Allen
authors.forename: Virginia
authors.initials: V
authors.lastname: Vega-Warner
authors.forename: Eric
authors.initials: E
authors.lastname: Wise
authors.forename: Heather M
authors.initials: HM
authors.lastname: Harville
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lyons
authors.forename: Joseph
authors.initials: J
authors.lastname: Washburn
authors.forename: James
authors.initials: J
authors.lastname: Macdonald
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
mesh_terms: D004252:DNA Mutational Analysis; D005189:False Positive Reactions; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D005819:Genetic Markers; D005828:Genetics, Population; D006720:Homozygote; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D009404:Nephrotic Syndrome / Q000235:genetics; D010375:Pedigree; D013256:Steroids / Q000494:pharmacology
chemical_list: D005819:Genetic Markers; D013256:Steroids