Dataset Information

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.

SUBMITTER: Koboldt DC

PROVIDER: S-EPMC3951946 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Exome-based mapping and variant prioritization for inherited Mendelian disorders.

Koboldt Daniel C DC Larson David E DE Sullivan Lori S LS Bowne Sara J SJ Steinberg Karyn M KM Churchill Jennifer D JD Buhr Aimee C AC Nutter Nathan N Pierce Eric A EA Blanton Susan H SH Weinstock George M GM Wilson Richard K RK Daiger Stephen P SP

American journal of human genetics 20140220 3

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 ...[more]

PMID: 24560519

Similar Datasets

Project description:Mendelian disorders are mostly caused by single mutations in the DNA sequence of a gene, leading to a phenotype with pathologic consequences. Whole Exome Sequencing of patients can be a cost-effective alternative to standard genetic screenings to find causative mutations of genetic diseases, especially when the number of cases is limited. Analyzing exome sequencing data requires specific expertise, high computational resources and a reference variant database to identify pathogenic variants.We developed a database of variations collected from patients with Mendelian disorders, which is automatically populated thanks to an associated exome-sequencing pipeline. The pipeline is able to automatically identify, annotate and store insertions, deletions and mutations in the database. The resource is freely available online http://exome.tigem.it. The exome sequencing pipeline automates the analysis workflow (quality control and read trimming, mapping on reference genome, post-alignment processing, variation calling and annotation) using state-of-the-art software tools. The exome-sequencing pipeline has been designed to run on a computing cluster in order to analyse several samples simultaneously. The detected variants are annotated by the pipeline not only with the standard variant annotations (e.g. allele frequency in the general population, the predicted effect on gene product activity, etc.) but, more importantly, with allele frequencies across samples progressively collected in the database itself, stratified by Mendelian disorder.We aim at providing a resource for the genetic disease community to automatically analyse whole exome-sequencing samples with a standard and uniform analysis pipeline, thus collecting variant allele frequencies by disorder. This resource may become a valuable tool to help dissecting the genotype underlying the disease phenotype through an improved selection of putative patient-specific causative or phenotype-associated variations.

Dataset Information

Exome-based mapping and variant prioritization for inherited Mendelian disorders.

Publications

Exome-based mapping and variant prioritization for inherited Mendelian disorders.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets