Development of Population-Based Screening for DiGeorge Syndrome Type 1

描述（由申请人提供）：据估计，1型DiGeorge综合征（DGS 1）是最常见的遗传性基因缺失综合征，每4,000例活产中有1例发生。这种常染色体显性遗传疾病具有广泛的临床特征，包括先天性心脏缺陷、咽喉异常、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，以及诊断性细胞遗传学荧光原位杂交（FISH）探针错过了DGS 1区域（染色体22q11.2）中至少15%的所有微缺失，DiGeorge综合征的诊断在大多数个体中被延迟。因此，据估计，只有25%的DGS 1患者在婴儿期被诊断，所有其他DGS 1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DGS 1相关的合并症。因此，迫切需要开发一种更灵敏和更具成本效益的DGS 1筛选方法。我们假设，从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DGS 1筛选测试。本研究的目的将集中在2个方面：目的1将集中在使用高密度SNP阵列准确定义大多数DGS 1受试者中发现的缺失边界和片段，并证明标准FISH细胞遗传学错过了比以前认识到的更大比例的DGS 1受试者。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测试，随后可以实施到DGS 1的州新生儿筛查计划中。 公共卫生相关性：我们相信这个建议与NIH的总体使命声明“延长健康生命，减少疾病和残疾的负担”非常吻合。“具体来说，我们的提案实现了NIH的路线图：1）支持改变和扩展我们对遗传性疾病的理解的项目，2）为个人健康提供潜在的直接和长期转化益处，3）促进独特的伙伴关系-在我们的情况下，CHW/MCW的科学家和医生科学家与威斯康星州卫生国家实验室的科学家之间的研究。我们的提案有两个主要目标。第一个目标是获得已知最常见的遗传缺失（DiGeorge综合征; DGS）的长期临床和遗传信息，影响该州每4，000名活产婴儿中就有1名。这些信息将使我们能够更好地检测和有效地治疗与DGS相关的多种合并症。我们的第二个目标，也是我们提案的主要目的，是成功开发一种敏感且具有成本效益的DGS新生儿筛查，可应用于州新生儿筛查计划。这是一个重要的目标，因为大多数DGS受试者未被诊断或误诊，随后患有与DGS相关的未经治疗的共病。我们坚信，通过在生命早期检测DGS受试者，它将允许适当的和潜在的挽救生命的医疗干预与DGS相关的许多残疾，如先天性心脏病和严重的免疫缺陷。

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.