Development of Population-Based Screening for DiGeorge Syndrome Type 1

描述(申请人提供)：DiGeorge综合征1型(DGS1)估计是最常见的遗传性遗传缺失综合征，每4,000名活产儿中就有1名发生。这种常染色体显性遗传病具有广泛的临床特征，包括先天性心脏病、腭咽闭合畸形、学习困难、内分泌异常、肾脏异常和免疫缺陷。不幸的是，由于这种不同的临床表型，以及诊断性细胞遗传学荧光原位杂交(FISH)探针至少遗漏了DGS1区域(染色体22q11.2)所有微缺失的15%，大多数人的DiGeorge综合征的诊断被推迟。因此，据估计，只有25%的DGS1患者是在婴儿时期被诊断出来的，而所有其他DGS1患者的诊断年龄中值为8岁。早期诊断和适当的医疗干预可以预防和有效治疗与DGS1相关的许多并存疾病。因此，迫切需要开发一种更灵敏、更经济的DGS1筛查方法。我们假设，最近开发的高密度单核苷酸多态(SNP)基因阵列产生的数据将允许开发有效的DGS1筛查测试。这项研究的目的将集中在两个领域：目标1将专注于使用高密度SNP阵列准确定义在大多数DGS1受试者中发现的缺失边界和片段，并证明标准FISH细胞遗传学错过的DGS1受试者比以前认识到的更大比例。目标2将侧重于开发一种高度敏感和成本效益高的筛查测试，随后可以将其落实到DGS1的国家新生儿筛查计划中。 与公共健康相关：我们认为这项建议很好地符合美国国立卫生研究院的总体使命声明，即延长健康寿命，减少疾病和残疾的负担。具体地说，我们的建议实现了NIH的路线图：1)支持转变和扩展我们对遗传疾病的理解的项目，2)为个人的健康提供潜在的即时和长期的翻译益处，3)促进独特的合作伙伴关系--在我们的情况下，是CHW/MCW的科学家和威斯康星州立卫生实验室的科学家之间的研究。我们的建议有两个主要目标。第一个目标是获取已知的最常见的基因缺失(DiGeorge综合征；DGS)的长期临床和遗传学信息，该州每4000名活产儿中就有一名受到影响。这些信息将使我们能够更好地发现和有效治疗与DGS相关的多种并存疾病。我们的第二个目标，也是我们提案的主要目的，是成功地开发出一种敏感且成本效益高的新生儿DGS筛查方法，可应用于国家新生儿筛查项目。这是一个重要的目标，因为大多数DGS受试者没有得到诊断或误诊，并随后患上与DGS相关的未经治疗的并存疾病。我们坚信，通过在生命早期检测DGS受试者，将允许对与DGS相关的许多残疾进行适当的、可能挽救生命的医疗干预，如先天性心脏病和严重免疫缺陷。

DESCRIPTION (provided by applicant): DiGeorge syndrome type 1 (DGS1) is estimated to be the most prevalent inheritable genetic deletion syndrome, occurring in 1 per 4,000 live births. A large range of clinical characteristics characterizes this autosomal dominant disease, including congenital heart defects, velopharyngeal abnormalities, learning difficulties, endocrine abnormalities, renal anomalies, and immune defects. Unfortunately the diagnosis of DiGeorge syndrome is delayed in most individuals because of this varying clinical phenotype, as well as the fact that the diagnostic cytogenetic fluorescent in situ hybridization (FISH) probe misses at least 15% of all microdeletions in the DGS1 region (chromosome 22q11.2). As a result, it is estimated that only 25% of DGS1 patients are diagnosed in infancy, with the median age of diagnosis for all other DGS1 patients being 8 years of age. Early diagnosis and appropriate medical intervention can prevent and effectively treat many of the co-morbidities associated with DGS1. Therefore, there is a critical need to develop a more sensitive and cost-effective screening method for DGS1. We hypothesize that data generated from recently developed high-density single-nucleotide polymorphism (SNP) genotype arrays will allow the development of effective screening tests for DGS1. The Aims of this study will focus on 2 areas: Aim 1 will focus on accurately defining the deletion boundries and segments found in the majority DGS1 subjects using high-density SNP arrays, and demonstrate that standard FISH cytogenetics misses a larger fraction of DGS1 subjects than previously appreciated. Aim 2 will focus on the development a highly sensitive and cost- effective screening test that can be subsequently implemented into a State Newborn Screening Program for DGS1. PUBLIC HEALTH RELEVANCE: We believe this proposal fits well with the overall mission statement of the NIH "to extend healthy life and reduce the burdens of illness and disability." Specifically, our proposal fulfills the NIH roadmap of 1) supporting projects that transform and extend our understanding of genetic disorders, 2) offering potential immediate and long-term translational benefit to the health of individuals, and 3) promoting unique partnerships - in our case, research between scientists and physician-scientists at CHW/MCW and scientists at the Wisconsin State Laboratory of Hygiene. There are two main goals of our proposal. The first goal is to acquire long-term clinical and genetic information of the most common genetic deletion known (DiGeorge syndrome; DGS), affecting 1 in 4,000 live births in the state. This information will allow us to better detect and effectively treat the multiple co-morbidities associated with DGS. Our second goal, and the main purpose of our proposal, is the successful development of a sensitive and cost-effective newborn screen for DGS that could be applied to State Newborn Screening Programs. This is an important goal since the majority of DGS subjects go undiagnosed or misdiagnosed, and subsequently suffer from untreated co- morbidities associated with DGS. We strongly believe that by detecting DGS subjects early in life, it will allow for proper and potentially life-saving medical interventions for the many disabilities associated with DGS, such as congenital heart disease and severe immunodeficiency.