Yale Center for Mendelian Disorders

描述（由申请人提供）：孟德尔疾病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3000多种此类疾病，人类基因组中有21,000个基因和约15%的胚胎致死位点，但显然仍有许多疾病有待发现。这既包括已描述的，也包括目前未描述的，对健康和疾病都有贡献的人类特征。在过去的12年里，DNA测序的成本下降了6倍，很明显，选择性地对基因组中的所有基因（仅占人类基因组的1%）进行测序是一种非常经济有效的方法，可以发现新的孟德尔疾病的基础。我们率先开发了外显子组测序方法和分析工具，并表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，预计在不久的将来低于1,000美元。我们已经证明了这种方法在识别一系列疾病基因方面的实用性，这些疾病基因以前由于基因定位困难而难以处理，原因是高位点异质性、新生突变或小型独一无二的家族。这些考虑激发了新的努力，利用这些技术有效地解决基本上所有的孟德尔特征。为此，我们建立了耶鲁孟德尔疾病中心，该中心将从已知或疑似孟德尔疾病的患者和家庭中确定和获取样本，测序外显子组的高覆盖率足以调用95%的高特异性变异，并使用我们设计的新的分析方法来识别新的孟德尔特征基因。我们将在允许的情况下向研究社区提供所有序列，并将建立一个网络界面，使医生和研究者能够提交研究样本并检索带注释的结果。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.