Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene

• DOI: 10.1371/journal.pgen.1000991
• Publication Date: 2010-06-17T16:39:14Z
• Authors: Nara L. M. Sobreira; Elizabeth T. Cirulli; Dimitrios Avramop...; Elizabeth Wohler; Gretchen L. Oswald; Eric L. Stevens; Dongliang Ge; Kevin V. Shianna; Jason P. Smith; Jessica M. Maia; Curtis E. Gumbs; Jonathan Pevsner; George Thomas; David Valle; Julie E. Hoover-Fong; David B. Goldstein
• Keywords: Mendelian inheritance; Proband; Nonsense mutation

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