Yale Center for Mendelian Disorders

描述（由申请人提供）：导致孟德尔疾病的突变的鉴定彻底改变了对每个器官系统疾病的理解。虽然在分子水平上已经解决了3,000多个这样的疾病，人类基因组中有21,000个基因，大约15%的胚胎致死基因座，但很明显，许多疾病仍有待发现。这包括描述和目前未描述的人类特征，有助于健康和疾病。随着DNA测序成本在过去12年中惊人的6个对数下降，已经变得明显的是，选择性地对基因组中的所有基因（其仅占人类基因组的~ 1%）进行测序代表了用于发现新孟德尔疾病的基础的非常具有成本效益的手段。我们率先开发了外显子组测序方法和分析工具，并已证明两者都是可扩展的，目前每个外显子组的成本低于1,500美元，预计在不久的将来将低于1,000美元。我们已经证明了这种方法的实用性与一系列的疾病基因的识别，以前是棘手的，由于基因定位的困难，由于高基因座异质性，从头突变，或小的一类家庭。这些考虑激发了新的努力，以有效地解决基本上所有孟德尔性状使用这些技术。为此，我们建立了耶鲁孟德尔疾病中心，该中心将确定和获取已知或疑似孟德尔疾病的患者和家庭的样本，对外显子组进行测序，以高覆盖率足以识别95%的具有高特异性的所有变体，并使用我们设计的新分析方法来识别新的孟德尔性状基因。我们将在允许的情况下向研究界提供所有序列，并将建立一个Web界面，使医生和研究人员能够提交研究样本并检索注释结果。这些研究将迅速扩大我们对人类疾病的基因和途径的理解。

DESCRIPTION (provided by applicant): The identification of mutations causing Mendelian diseases has revolutionized the understanding of diseases of every organ system. While over 3,000 such diseases have been solved at the molecular level, with 21,000 genes in the human genome and about 15% embryonic lethal loci, it is clear that many remain to be discovered. This includes both described and presently undescribed human traits that contribute to both health and disease. With the spectacular 6-log drop in the cost of DNA sequencing over the last 12 years, it has become apparent that selectively sequencing all of the genes in the genome, which comprise only ~1 % of the human genome represents a very cost-effective means for discovering the basis of new Mendelian diseases. We have pioneered the development of the exome sequencing method as well as the tools for analysis, and have shown that both are scalable, with current cost under $1,500 per exome and expected to be under $1,000 in the near future. We have demonstrated the utility of this approach with the identification of a range of disease genes that were previously intractable due to difficulties in gene mapping owing to high locus heterogeneity, de novo mutations, or small one-of-a-kind families. These considerations motivate new efforts to efficiently solve substantially all Mendelian traits using these technologies. To this end we have established the Yale Center for Mendelian Disorders which will ascertain and acquire samples from patients and families with known or suspected Mendelian diseases, sequence exomes to high coverage sufficient to call 95% of all variants with high specificity and use new analytic approaches we have devised to identify new Mendelian trait genes. We will make all sequences available to the research community as allowed and will establish a Web interface to enable physicians and investigators to submit research samples and retrieve annotated results. These studies will rapidly expand our understanding of the genes and pathways underlying human disease.