Exome sequencing identifies the cause of a Mendelian disorder
Sarah B H Ng,Kati J. Buckingham,Choli Lee,Abigail W. Bigham,Holly K. Tabor,Holly K. Tabor,Karin M. Dent,Chad D. Huff,Paul Shannon,Ethylin Wang Jabs,Ethylin Wang Jabs,Deborah A. Nickerson,Jay Shendure,Michael J. Bamshad,Michael J. Bamshad +14 more
TLDR
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.Abstract:
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 40x and sufficient depth to call variants at approximately 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.read more
Citations
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ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data
TL;DR: The ANNOVAR tool to annotate single nucleotide variants and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP is developed.
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A framework for variation discovery and genotyping using next-generation DNA sequencing data
Mark A. DePristo,Eric Banks,Ryan Poplin,Kiran V. Garimella,Jared Maguire,Christopher Hartl,Anthony A. Philippakis,Anthony A. Philippakis,Anthony A. Philippakis,Guillermo del Angel,Manuel A. Rivas,Manuel A. Rivas,Matt Hanna,Aaron McKenna,Timothy Fennell,Andrew Kernytsky,Andrey Sivachenko,Kristian Cibulskis,Stacey Gabriel,David Altshuler,David Altshuler,Mark J. Daly,Mark J. Daly +22 more
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Predicting the Functional Effect of Amino Acid Substitutions and Indels
TL;DR: A new algorithm, PROVEAN (Protein Variation Effect Analyzer), is developed, which provides a generalized approach to predict the functional effects of protein sequence variations including single or multiple amino acid substitutions, and in-frame insertions and deletions.
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TL;DR: A DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes, showing its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.
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BEDTools: The Swiss‐Army Tool for Genome Feature Analysis
TL;DR: The BEDTools toolkit as discussed by the authors is a toolkit for the exploration of high-throughput genomics datasets, which can be combined to create bespoke pipelines addressing complex questions.
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