Exome sequencing identifies the cause of a Mendelian disorder

By Sarah B. H. Ng, K. Buckingham, Choli Lee, Abigail W. Bigham, H. Tabor, K. Dent, C. Huff, Paul T. Shannon, E. Jabs, Deborah A. Nickerson and 2 more. Nature Genetics, 2009

2,093 citations recorded by the source corpus.

We demonstrate the first successful application of exome sequencing to discover the gene for a rare mendelian disorder of unknown cause, Miller syndrome (MIM%263750). For four affected individuals in three independent kindreds, we captured and sequenced coding regions to a mean coverage of 40× and sufficient depth to call variants at ∼97% of each targeted exome. Filtering against public SNP databases and eight HapMap exomes for genes with two previously unknown variants in each of the four individuals identified a single candidate gene, DHODH, which encodes a key enzyme in the pyrimidine de novo biosynthesis pathway. Sanger sequencing confirmed the presence of DHODH mutations in three additional families with Miller syndrome. Exome sequencing of a small number of unrelated affected individuals is a powerful, efficient strategy for identifying the genes underlying rare mendelian disorders and will likely transform the genetic analysis of monogenic traits.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8faf969546fdc774ebd07b8f7f7e83de29b4f09f

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Citations in the corpus

Exome sequencing as a tool for Mendelian disease gene discovery (2011, neutral): “In less than 2 years, exome sequencing has been used to identify causal alleles for several dozen Mendelian disorders 2,11, 15– 38 ( Supplementary information 1 ( table Underlying this method is the assumption that the filter set contains no alleles from individuals with the phenotype being studied.”
BEDTools: the Swiss-army tool for genome feature analysis (2014, background): “For example, exome capture kits focus the sequence budget on the 1% to 2% of the genome that encodes protein-coding genes and UTRs (Ng et al., 2010).”
A scalable, fully automated process for construction of sequence-ready human exome targeted capture libraries (2011, background): “Key applications for targeted approaches include sequencing of exons or sets of protein-coding genes implicated in specific diseases [18-21], whole human exome sequencing (for example, in cancer or disease cohorts) [22-24] (reviewed in [25]), and resequencing of specific regions as a follow-up to ge”
Computational tools for copy number variation (CNV) detection using next-generation sequencing data: features and perspectives (2013, background): “Due to investigators’ interest in coding gene regions and its lower cost, WES is widely applied to Mendelian as well as other complex diseases [48].”
Predicting the Functional Effect of Amino Acid Substitutions and Indels (2012, methodology): “to remove commonly occurring polymorphisms in the human populations, and prediction tools for coding variants are used to provide assessments on the impact of the genetic variants on protein function [25,27,29].”
Low concordance of multiple variant-calling pipelines: practical implications for exome and genome sequencing (2013, background): “Previous calculations have estimated the average expected number of de novo non-synonymous coding mutations per individual exome to be approximately 1 to 2 [27-30].”
dbNSFP: A Lightweight Database of Human Non-synonymous SNPs and Their Functional Predictions (2011, methodology): “Functional predictions or conservation information are used to filter or prioritize the novel NSs for further analysis or confirmation [Ng et al., 2010].”
Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome (2010, positive): “646" language="eng" relation="no"> We demonstrate the successful application of exome sequencin”