Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene.
Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene.
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DOI：
10.1371/journal.pgen.1000991
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发表时间：
2010-06-17
期刊：
影响因子：
4.5
通讯作者：
Goldstein DB
中科院分区：
文献类型：
--
作者：
Sobreira NL;Cirulli ET;Avramopoulos D;Wohler E;Oswald GL;Stevens EL;Ge D;Shianna KV;Smith JP;Maia JM;Gumbs CE;Pevsner J;Thomas G;Valle D;Hoover-Fong JE;Goldstein DB
尽管已有超过2400个基因被证明含有导致孟德尔疾病的变异体，但仍有数千种此类疾病尚未从分子层面得到定义。新的全基因组测序技术能够快速识别任何给定基因组中的大多数基因变异体，这为识别这些疾病基因提供了一个令人兴奋的机会。在此，我们对一名患有显性孟德尔疾病——多发性内生软骨瘤病（OMIM 156250）的患者的整个基因组进行了测序，并利用其小家庭的部分连锁数据来聚焦我们对致病变异体的搜索。在该先证者中，我们在PTPN11基因的第4外显子中发现了一个11bp的缺失，这改变了阅读框，导致翻译提前终止，并与表型共分离。在第二个多发性内生软骨瘤病家庭中，我们通过在PTPN11基因第4外显子中识别出一个无义突变，且该突变也与表型共分离，从而证实了我们的结果。对469名对照者的PTPN11基因第4外显子进行测序，未发现此类蛋白质截断变异体，这支持了这两种突变的致病性。这种新技术与经典遗传学方法的结合为发现导致不明原因孟德尔疾病的基因提供了一种强有力的策略。
多发性内生软骨瘤病（MC）是一种常染色体显性遗传病，其特征是外生骨疣（骨软骨瘤），通常发生在手和脚，以及长骨干骺端和髂嵴的内生软骨瘤。MC的外生骨疣可能会随时间消退甚至消失，身材矮小不是MC的特征。在此，我们对一名MC患者的整个基因组进行了测序，并利用其小家庭的部分连锁数据来聚焦我们对致病变异体的搜索。在该先证者中，我们在PTPN11基因的第4外显子中发现了一个11bp的缺失，这导致翻译提前终止，并与表型共分离。在第二个多发性内生软骨瘤病家庭中，我们在PTPN11基因第4外显子中识别出一个无义突变，该突变也与表型共分离。PTPN11基因的种系功能获得性错义突变会导致一组有重叠但不同的显性疾病，涉及面部、心脏、骨骼、皮肤和大脑，包括努南综合征（OMIM 163950）、伴有多发性巨细胞病变综合征的类努南综合征（OMIM 163955）和豹皮综合征（OMIM 151100）。PTPN11基因的无义突变在人类中尚未有描述，我们在此报告的PTPN11基因功能丧失性突变是在人类疾病中首次被描述。
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. Metachondromatosis (MC) is an autosomal dominant condition characterized by exostoses (osteochondromas), commonly of the hands and feet, and enchondromas of long bone metaphyses and iliac crests. MC exostoses may regress or even resolve over time, and short stature is not characteristic of MC. Here, we sequenced the whole genome of a single patient with MC 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 results in premature translation termination and co-segregates with the phenotype. In a second metachondromatosis family, we identified a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Germline gain-of-function missense mutations in PTPN11 cause an overlapping but distinct group of dominant disorders with involvement of the face, heart, skeleton, skin, and brain, including Noonan syndrome (OMIM 163950), Noonan-like disorder with multiple giant cell lesion syndrome (OMIM 163955), and LEOPARD syndrome (OMIM 151100). Nonsense mutations in PTPN11 have not been described in humans and the loss-of-function PTPN11 mutations we report here are the first to be described in human disease.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.5
作者：
Oishi, Kimihiko;Zhang, Hui;Gelb, Bruce D.
通讯作者：
Gelb, Bruce D.
影响因子：
19.7
作者：
KENNEDY, LA
通讯作者：
KENNEDY, LA
DOI：
10.2106/00004623-198567050-00022
发表时间：
1985-01-01
影响因子：
5.3
作者：
BASSETT, GS;COWELL, HR
通讯作者：
COWELL, HR
DOI：
10.1007/bf00442274
发表时间：
1971-01-01
期刊：
ZEITSCHRIFT FUR KINDERHEILKUNDE
影响因子：
--
作者：
MAROTEAUX, P
通讯作者：
MAROTEAUX, P