Phenotypic and Genotypic Analyses of Genetic Skin Disease through the Online Mendelian Inheritance in Man (OMIM) Database
Phenotypic and Genotypic Analyses of Genetic Skin Disease through the Online Mendelian Inheritance in Man (OMIM) Database
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DOI：
10.1038/jid.2009.108
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发表时间：
2009-11-01
影响因子：
6.5
通讯作者：
Tsao, Hensin
中科院分区：
文献类型：
--
作者：
Feramisco, Jamison D.;Sadreyev, Ruslan I.;Tsao, Hensin
尽管在基因组技术和基因型解析方面取得了前所未有的进展，但我们捕获疾病“表型组”的能力仍然面临巨大挑战。“我们提出了一种以前从未报道过的方法，用于将人类疾病解卷积为基本特征，从而创建与疾病和基因型空间相互作用的第三个空间。使用皮肤和非皮肤的临床研究结果，通过约翰霍普金斯大学的在线孟德尔遗传在人（OMIM）数据库，我们开始解构遗传性皮肤病（GSD）到其各个组成部分，更充分地探讨这些功能之间的关系，在复杂的表型空间和表征的基因型空间内，这些疾病的存在。使用OMIM，我们将GSD的当前状态定义为包括与501个独特的蛋白质编码基因相关的560种不同的疾病。最常见的基本皮肤特征包括角质化、糜烂和毛发/指甲表型，最常见的全身特征包括与发育、肌肉骨骼和神经系统相关的特征。作为一个原则的证明，我们集中在一个单一的皮肤特征-咖啡牛奶斑-并根据这一发现将疾病空间划分为层次分组。最后，GSD基因座之间的功能分析被映射回皮肤功能，提供洞察到色素和听觉功能。表型去卷积提供了一个分析医学疾病的框架，并可以帮助组织和阐明与人类疾病相关的生物学机制。
Despite unprecedented gains in genomic technologies and genotype resolution, there remain tremendous challenges in our ability to capture disease "phenomes.'' We propose a previously unreported method for deconvolving human disease into elemental features, thereby creating a third space that interacts with both the disease and genotypic spaces. Using cutaneous and noncutaneous clinical findings available through Johns Hopkins University's Online Mendelian Inheritance in Man (OMIM) database, we set out to deconstruct genetic skin disease (GSD) into its various components, to more fully explore the relationship between these features within the complex phenotypic space and to characterize the genotypic space within which these disorders exist. Using OMIM, we defined the current state of GSD as including 560 distinct disorders associated with 501 unique protein-encoding genes. The most common elemental skin features included cornifying, erosive, and hair/nail phenotypes, and the most common systemic features included those associated with developmental, musculoskeletal, and neurological systems. As a proof of principle, we focused on a single skin feature-cafe-au-lait macules-and partitioned the disease space into hierarchical groupings on the basis of this finding. Finally, functional analyses among GSD loci were mapped back to skin features, providing insights into pigmentary and auditory features. Phenotypic deconvolution provides a framework for analyzing medical disorders and can aid in the organization and elucidation of biological mechanisms related to human disease.