title: Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene.
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.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Nara L M
authors.initials: NL
authors.lastname: Sobreira
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Cirulli
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramopoulos
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wohler
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Oswald
authors.forename: Eric L
authors.initials: EL
authors.lastname: Stevens
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Jason P
authors.initials: JP
authors.lastname: Smith
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Maia
authors.forename: Curtis E
authors.initials: CE
authors.lastname: Gumbs
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pevsner
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: David
authors.initials: D
authors.lastname: Valle
authors.forename: Julie E
authors.initials: JE
authors.lastname: Hoover-Fong
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D005091:Exons; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11