AUTOMATED DETECTION OF GENE DUPLICATIONS OR DELETIONS

该项目将开发自动化仪器和图像分析技术，以在间期FISH中检测常规细胞遗传学难以检测到的基因复制或缺失。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。这些疾病包括：(1)神经疾病；Charcot-Marie-Tooth病(CMT1A)和遗传性神经病变伴压力性瘫痪(HNPP)；(2)神经疾病；Pelizaeus-Merzbacher病(PMD)和X连锁痉挛截瘫(SPG2)；(3)肌肉萎缩障碍；Duchene(DMD)和Becker肌营养不良(BMD)；(4)邻近基因综合征；Smith-Magenis综合征(SMS)。我们的方法是使用现成的DNA探针，然后进行自动基因筛查，以检测复制/缺失。我们将开发一种自动识别间期细胞的成像系统，并使用复杂的图像分析来高分辨率检测和分离微观重排。第一阶段项目将评估自动成像系统的可行性，并评估鱼点识别和分离的效率和精度。第二阶段将建造并在临床上测试原型。第三阶段将使该仪器商业化。这种结合了创新的鱼点检测算法的高分辨率成像系统，具有成为检测基因复制/缺失的主要筛查方法的巨大潜力。计算机自动化将通过降低成本和将人类从繁琐的工作中解脱出来，使基因筛查变得大规模实用。这种方法对医学遗传学，特别是对CMT1A/HNPP、PMD/SPG2、DMD/BMD、SMS的筛查将是最有价值的。拟议的商业应用：一旦这些技术被开发出来并符合常规应用的条件，它们将被整合到PSI的细胞遗传学自动化设备的Powergene产品线中，用于出售的新系统，并作为对细胞遗传学实验室已在使用的现有系统的升级。因此，在该项目下开发的技术将很快实现商业化。

This project will develop automated instrumentation and image analysis techniques to detect, in interphase FISH, gene duplications or deletions 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. The Phase I project will evaluate feasibility of the automated imaging system, and evaluate the efficiency and precision of FISH dot identification and separation. Phase II will build and test a prototype clinically. Phase III will commercialize the instrument. This high resolution imaging system, incorporating innovative FISH dot detection algorithms,has tremendous potential to become a primary screening method for detecting gene duplications/deletions. 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, SMS. PROPOSED COMMERCIAL APPLICATIONS: As soon as the techniques are developed and qualified for routine application, they will be incorporated into PSI's PowerGene product line of cytogenetics automation equipment, both in new systems sold and as an upgrade to existing systems already in use in cytogenetics labs. Thus, commercialization of the technology developed under this project will occur quickly.