Automated Detection of Gene Duplications or Deletions

自动检测基因重复或缺失

• 批准号: 6874478
• 负责人: Fatima Aziz Merchant
• 金额: $ 35.99万
• 依托单位: ADVANCED DIGITAL IMAGING RESEARCH, LLC
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2007-03-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874478
• 关键词: Smith Magenis syndrome; bioimaging /biomedical imaging; biomedical automation; biomedical equipment development; clinical research; computer program /software; digital imaging; fluorescence microscopy; fluorescent in situ hybridization; gene deletion mutation; gene duplication; genetic screening; hereditary motor and sensory neuropathy; human subject; imaging /visualization /scanning; leukodystrophy; molecular probes; myotonic dystrophy; nucleic acid probes; three dimensional imaging /topography

DESCRIPTION (provided by applicant): This project will further develop automated instrumentation and image analysis techniques to detect gene duplications or deletions in interphase FISH, which are difficult to detect by routine cytogenetics. There is a growing list of genetic disorders that result from chromosomal anomalies, related to either duplications or deletions. These include: (1) neuropathies; Charcot-Marie-Tooth Disease (CMT1A) and Hereditary Neuropathy with Pressure Palsies (HNPP), (2) neurological disorders; Pelizaeus-Merzbacher Disease (PMD) and X-Linked Spastic Paraplegia (SPG2), (3) muscular wasting disorders; Duchene (DMD) and Becker Muscular Dystrophy (BMD), (4) contiguous-gene syndromes; Smith-Magenis Syndrome (SMS). Our approach is to use readily available DNA probes, followed by automated genetic screening to detect duplications/deletions. We will develop an imaging system for the automated identification of interphase cells, and use sophisticated image analysis for high-resolution detection and separation of microscopic rearrangements. In the Phase I project we evaluated the feasibility of newly developed imaging algorithms, for effectively and precisely identifying the separation of FISH dot duplicates. Algorithms were developed for automatically (1) segmenting dots, (2) computing the integrated fluorescence intensity of dots, (3) determining the separation distance, and (4) classifying duplicates and single dots. In Phase II we will incorporate the newly developed imaging algorithms into our automated imaging system, and test the prototype clinically. We will also develop and implement three-dimensional modeling techniques to obtain an unbiased estimate of the spatial distance between duplicated genes. Phase III will commercialize the instrument. Computer automation will make genetic screening practical on a large scale by reducing costs and relieving humans of tedious duties. This approach will be most valuable to medical genetics, particularly for screening CMT1A/HNPP, PMD/SPG2, DMD/BMD, and SMS. Duplications have also been identified for the Prader-Willi /Angelman syndrome region that result in autism. Duplications, such as for 22ql 1.2 and 17pl 1.2 have been described and result in a rather mild phenotype. But duplications of the Williams syndrome region have not been described and thus, the phenotype is unknown. The ability to screen patients for duplications by interphase FISH analysis will likely identify a large number of individuals that would benefit from medical intervention. It may uncover syndromes that previously had no identifiable etiology. This will provide a screening test and eventually a diagnostic test for those individuals with perhaps mild phenotypes, such as learning disabilities.

描述（由申请人提供）： 本项目将进一步开发自动化仪器和图像分析技术，以检测间期FISH中常规细胞遗传学难以检测的基因重复或缺失。越来越多的遗传疾病是由染色体异常引起的，与复制或缺失有关。其中包括：（1）神经病变;腓骨肌萎缩症（CMT 1A）和遗传性神经病伴压力性麻痹（HNPP），（2）神经系统疾病;佩-梅二氏病（PMD）和X连锁痉挛性截瘫（SPG 2），（3）肌肉消耗性疾病;杜切尼（DMD）和贝克尔肌营养不良症（BMD），（4）邻接基因综合征;史密斯-马格尼斯综合征（SMS）。 我们的方法是使用现成的DNA探针，然后进行自动遗传筛查，以检测重复/缺失。我们将开发一种用于间期细胞自动识别的成像系统，并使用复杂的图像分析进行高分辨率检测和分离显微重排。 在第一阶段的项目中，我们评估了新开发的成像算法的可行性，有效地和精确地识别分离的FISH点重复。开发了用于自动（1）分割点、（2）计算点的积分荧光强度、（3）确定分离距离和（4）对重复点和单个点进行分类的算法。 在第二阶段，我们将把新开发的成像算法整合到我们的自动成像系统中，并对原型进行临床测试。我们还将开发和实施三维建模技术，以获得重复基因之间的空间距离的无偏估计。第三阶段将使该仪器商业化。 计算机自动化将通过降低成本和减轻人类繁琐的工作，使基因筛查在大规模上变得实用。该方法对医学遗传学，特别是对CMT 1A/HNPP、PMD/SPG 2、DMD/BMD和SMS的筛查具有重要价值。普拉德-威利/安吉尔曼综合征区域也发现了导致自闭症的重复。已经描述了诸如22 ql 1.2和17 pl 1.2的重复，并导致相当温和的表型。但是威廉姆斯综合征区域的重复还没有被描述，因此，表型是未知的。通过间期FISH分析筛选重复患者的能力可能会识别出大量受益于医疗干预的个体。它可以发现以前没有可识别病因的综合征。这将提供一个筛选测试，并最终为那些可能具有轻度表型的个体提供诊断测试，例如学习障碍。