據了解，混合性軟骨瘤病是一種罕見的遺傳疾病。杜克大學醫學中心的研究人員結合新的全基因組測序技術和經典遺傳學方法發現了兩個導致混合性軟骨瘤病的基因變異。據介紹，研究人員只對一個個體進行了全基因組測序分析，該研究結果發布在PLoS Genetics雜志上。

對罕見遺傳疾病（有時候稱"孟德爾遺傳"疾病）的研究，傳統的方式主要是使用一種叫"連鎖分析"（ linkage）的方法，該方法使用少量的標簽對疾病遺傳性進行評估。目前，這種方法已成功應用于很多案例，但是它很耗時，且在1500多項被懷疑是孟德爾遺傳疾病的研究中被證明是失敗的。

Goldstein介紹說，"他的團隊使用一種新的策略發現了導致混合性軟骨瘤病的變異，并快速地識別了該遺傳基因。更為重要的是，該策略允許我們識別許多傳統方法很難識別的遺傳基因。"

研究小組選擇了家族中的一個成員進行全基因組測序。然后，他們使用從其他家族成員中獲得的部分連鎖數據識別出基因組中可能是變異潛在成因的區域。由于遺傳物質的數量巨大，很難用傳統的方法完成測序。

結果表明，所有患有混合性軟骨瘤病的家族成員都攜帶有一種叫PTPN11的基因的變異。在一個有疾病史的家族中研究人員發現相同基因上存在一個不同的變異，這就證實了PTPN11改變是疾病的發病原因。研究人員猜測，這兩個變異導致了功能丟失，或者身體缺陷而不能產生正常發育的一種必要蛋白。

在469個無關聯的參照個體中，研究人員對PTPN11的外顯子4，即變異位點進行測序，結果并沒有發現這個基因在該組中的任何變異。

這項研究表明，全基因組測序方法也可以成功識別了罕見的高滲透疾病風險因子。Goldstein表示，希望這種基于家族的測序技術能夠用于一些更為常見的疾病的遺傳變異研究。

上海勁馬生物推薦原文出處：

PLoS Genetics doi:10.1371/journal.pgen.1000991

Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene
Nara L. M. Sobreira1,2#, Elizabeth T. Cirulli3#, Dimitrios Avramopoulos1,4#, Elizabeth Wohler5, Gretchen L. Oswald1, Eric L. Stevens1,2, Dongliang Ge3, Kevin V. Shianna3, Jason P. Smith3, Jessica M. Maia3, Curtis E. Gumbs3, Jonathan Pevsner6,7, George Thomas1,5, David Valle1,8?, Julie E. Hoover-Fong1,8,9?, David B. Goldstein2?*

1 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 2 Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 3 Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, United States of America, 4 Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 5 Department of Cytogenetics, Kennedy Krieger Institute, Baltimore, Maryland, United States of America, 6 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 7 Department of Neurology, Kennedy Krieger Institute, Baltimore, Maryland, United States of America, 8 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 9 Greenberg Center for Skeletal Dysplasias, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America

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.