Exome sequencing identifies the cause of a mendelian disorder

Sarah B. Ng, Kati J. Buckingham, Choli Lee, Abigail W. Bigham, Holly K. Tabor, Karin M. Dent, Chad D. Huff, Paul T. Shannon, Ethylin Wang Jabs, Deborah A. Nickerson, Jay Shendure, Michael J. Bamshad

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)30-35
Number of pages6
JournalNature Genetics
Volume42
Issue number1
DOIs
StatePublished - Jan 2010

Fingerprint

Exome
Genes
HapMap Project
Single Nucleotide Polymorphism
Databases
Mutation
Enzymes
Genee-Wiedemann syndrome

ASJC Scopus subject areas

  • Genetics

Cite this

Ng, S. B., Buckingham, K. J., Lee, C., Bigham, A. W., Tabor, H. K., Dent, K. M., ... Bamshad, M. J. (2010). Exome sequencing identifies the cause of a mendelian disorder. Nature Genetics, 42(1), 30-35. https://doi.org/10.1038/ng.499

Exome sequencing identifies the cause of a mendelian disorder. / Ng, Sarah B.; Buckingham, Kati J.; Lee, Choli; Bigham, Abigail W.; Tabor, Holly K.; Dent, Karin M.; Huff, Chad D.; Shannon, Paul T.; Jabs, Ethylin Wang; Nickerson, Deborah A.; Shendure, Jay; Bamshad, Michael J.

In: Nature Genetics, Vol. 42, No. 1, 01.2010, p. 30-35.

Research output: Contribution to journalArticle

Ng, SB, Buckingham, KJ, Lee, C, Bigham, AW, Tabor, HK, Dent, KM, Huff, CD, Shannon, PT, Jabs, EW, Nickerson, DA, Shendure, J & Bamshad, MJ 2010, 'Exome sequencing identifies the cause of a mendelian disorder', Nature Genetics, vol. 42, no. 1, pp. 30-35. https://doi.org/10.1038/ng.499
Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM et al. Exome sequencing identifies the cause of a mendelian disorder. Nature Genetics. 2010 Jan;42(1):30-35. https://doi.org/10.1038/ng.499
Ng, Sarah B. ; Buckingham, Kati J. ; Lee, Choli ; Bigham, Abigail W. ; Tabor, Holly K. ; Dent, Karin M. ; Huff, Chad D. ; Shannon, Paul T. ; Jabs, Ethylin Wang ; Nickerson, Deborah A. ; Shendure, Jay ; Bamshad, Michael J. / Exome sequencing identifies the cause of a mendelian disorder. In: Nature Genetics. 2010 ; Vol. 42, No. 1. pp. 30-35.
@article{d154e626e8e0472aba6c3bfe89ab9481,
title = "Exome sequencing identifies the cause of a mendelian disorder",
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 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.",
author = "Ng, {Sarah B.} and Buckingham, {Kati J.} and Choli Lee and Bigham, {Abigail W.} and Tabor, {Holly K.} and Dent, {Karin M.} and Huff, {Chad D.} and Shannon, {Paul T.} and Jabs, {Ethylin Wang} and Nickerson, {Deborah A.} and Jay Shendure and Bamshad, {Michael J.}",
year = "2010",
month = "1",
doi = "10.1038/ng.499",
language = "English (US)",
volume = "42",
pages = "30--35",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Exome sequencing identifies the cause of a mendelian disorder

AU - Ng, Sarah B.

AU - Buckingham, Kati J.

AU - Lee, Choli

AU - Bigham, Abigail W.

AU - Tabor, Holly K.

AU - Dent, Karin M.

AU - Huff, Chad D.

AU - Shannon, Paul T.

AU - Jabs, Ethylin Wang

AU - Nickerson, Deborah A.

AU - Shendure, Jay

AU - Bamshad, Michael J.

PY - 2010/1

Y1 - 2010/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=73349110071&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73349110071&partnerID=8YFLogxK

U2 - 10.1038/ng.499

DO - 10.1038/ng.499

M3 - Article

VL - 42

SP - 30

EP - 35

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -