title: Exome-based mapping and variant prioritization for inherited Mendelian disorders.
abstract: Exome sequencing in families affected by rare genetic disorders has the potential to rapidly identify new disease genes (genes in which mutations cause disease), but the identification of a single causal mutation among thousands of variants remains a significant challenge. We developed a scoring algorithm to prioritize potential causal variants within a family according to segregation with the phenotype, population frequency, predicted effect, and gene expression in the tissue(s) of interest. To narrow the search space in families with multiple affected individuals, we also developed two complementary approaches to exome-based mapping of autosomal-dominant disorders. One approach identifies segments of maximum identity by descent among affected individuals; the other nominates regions on the basis of shared rare variants and the absence of homozygous differences between affected individuals. We showcase our methods by using exome sequence data from families affected by autosomal-dominant retinitis pigmentosa (adRP), a rare disorder characterized by night blindness and progressive vision loss. We performed exome capture and sequencing on 91 samples representing 24 families affected by probable adRP but lacking common disease-causing mutations. Eight of 24 families (33%) were revealed to harbor high-scoring, most likely pathogenic (by clinical assessment) mutations affecting known RP genes. Analysis of the remaining 17 families identified candidate variants in a number of interesting genes, some of which have withstood further segregation testing in extended pedigrees. To empower the search for Mendelian-disease genes in family-based sequencing studies, we implemented them in a cross-platform-compatible software package, MendelScan, which is freely available to the research community.
authors.affiliation: The Genome Institute at Washington University, St. Louis, MO 63108, USA. Electronic address: dkoboldt@genome.wustl.edu.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.affiliation: The Genome Institute at Washington University, St. Louis, MO 63108, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Larson
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, TX 77025, USA.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Sullivan
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, TX 77025, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bowne
authors.affiliation: The Genome Institute at Washington University, St. Louis, MO 63108, USA.
authors.forename: Karyn M
authors.initials: KM
authors.lastname: Steinberg
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, TX 77025, USA.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Churchill
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, TX 77025, USA.
authors.forename: Aimee C
authors.initials: AC
authors.lastname: Buhr
authors.affiliation: The Genome Institute at Washington University, St. Louis, MO 63108, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Nutter
authors.affiliation: Ocular Genomics Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
authors.affiliation: Hussman Institute of Human Genomics, University of Miami, Miami, FL 33101, USA.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
authors.affiliation: The Genome Institute at Washington University, St. Louis, MO 63108, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Weinstock
authors.affiliation: The Genome Institute at Washington University, St. Louis, MO 63108, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, TX 77025, USA. Electronic address: stephen.p.daiger@uth.tmc.edu.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Daiger
mesh_terms: D002874:Chromosome Mapping / Q000379:methods*; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D008040:Genetic Linkage; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics*; D012984:Software
chemical_list: D005819:Genetic Markers