Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene.

Nara Sobreira, Elizabeth T. Cirulli, Dimitrios Avramopoulos, Elizabeth Wohler, Gretchen L. Oswald, Eric L. Stevens, Dongliang Ge, Kevin V. Shianna, Jason P. Smith, Jessica M. Maia, Curtis E. Gumbs, Jonathan A. Pevsner, George Thomas, David Valle, Julie E Hoover Fong, David B. Goldstein

Research output: Contribution to journalArticle

Abstract

Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders.

Original languageEnglish (US)
JournalPLoS Genetics
Volume6
Issue number6
DOIs
StatePublished - 2010

Fingerprint

exons
linkage (genetics)
genome
Genome
Exons
phenotype
gene
mutation
Genes
nonsense mutation
genes
pathogenicity
Technology
Genetic Databases
Phenotype
translation (genetics)
Aptitude
Nonsense Codon
Information Storage and Retrieval
Virulence

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. / Sobreira, Nara; Cirulli, Elizabeth T.; Avramopoulos, Dimitrios; Wohler, Elizabeth; Oswald, Gretchen L.; Stevens, Eric L.; Ge, Dongliang; Shianna, Kevin V.; Smith, Jason P.; Maia, Jessica M.; Gumbs, Curtis E.; Pevsner, Jonathan A.; Thomas, George; Valle, David; Hoover Fong, Julie E; Goldstein, David B.

In: PLoS Genetics, Vol. 6, No. 6, 2010.

Research output: Contribution to journalArticle

Sobreira, Nara ; Cirulli, Elizabeth T. ; Avramopoulos, Dimitrios ; Wohler, Elizabeth ; Oswald, Gretchen L. ; Stevens, Eric L. ; Ge, Dongliang ; Shianna, Kevin V. ; Smith, Jason P. ; Maia, Jessica M. ; Gumbs, Curtis E. ; Pevsner, Jonathan A. ; Thomas, George ; Valle, David ; Hoover Fong, Julie E ; Goldstein, David B. / Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. In: PLoS Genetics. 2010 ; Vol. 6, No. 6.
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