Development of Population-Based Screening for DiGeorge Syndrome Type 1

描述（由申请人提供）：diggeorge综合征1型（DGS1）估计是最普遍的遗传性基因缺失综合征，每4000个活产婴儿中有1个发生。这种常染色体显性遗传病具有广泛的临床特征，包括先天性心脏缺陷、腭咽异常、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，以及诊断细胞遗传学荧光原位杂交（FISH）探针在DGS1区域（染色体22q11.2）的所有微缺失中至少有15%被遗漏，因此在大多数个体中DiGeorge综合征的诊断被延迟。因此，据估计，只有25%的DGS1患者在婴儿期被诊断出来，而所有其他DGS1患者的中位诊断年龄为8岁。早期诊断和适当的医疗干预可以预防和有效治疗许多与DGS1相关的合并症。因此，迫切需要开发一种更敏感和更具成本效益的DGS1筛选方法。我们假设，最近开发的高密度单核苷酸多态性（SNP）基因型阵列产生的数据将允许开发有效的DGS1筛选试验。本研究的目标将集中在两个方面：目标1将集中于使用高密度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细胞遗传学缺失DGS1受试者的比例比之前所认为的要大。目标2将侧重于开发一种高度敏感和具有成本效益的筛查方法，该方法可随后在DGS1的国家新生儿筛查计划中实施。

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.