A novel approach for diagnosis and newborn screening for 22q11 deletion syndrome

22q11 缺失综合征诊断和新生儿筛查的新方法

• 批准号: 7688527
• 负责人: LISA J. KOBRYNSKI
• 金额: $ 7.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688527
• 关键词: 22q; 22q11; 22q11 Deletion Syndrome; 22q11.2; Adolescence; Affect; Biological Assay; Birth; Blood; Childhood; Chromosomes, Human, Pair 22; Complex; Congenital Heart Defects; DNA; DNA Probes; Detection; Development; DiGeorge Syndrome; Diagnosis; Disease; Dyes; Early treatment; Fluorescent in Situ Hybridization; Frequencies; Goals; Hypoparathyroidism; Incidence; Individual; Label; Live Birth; Measures; Medical; Neonatal Screening; Newborn Infant; Patients; Population; Relative (related person); Running; Sampling; Schizophrenia; Schools; Screening procedure; Sensitivity and Specificity; Shprintzen syndrome; Speech Delay; Spottings; Syndrome; Testing; Time; Whole Blood; case control; cohort; microdeletion; novel strategies; population based; public health relevance; thymic aplasia

DESCRIPTION (provided by applicant): Digeorge syndrome/Velocardiofacial syndrome/22q11.2 deletion syndrome is a complex disorder due to a microdeletion of 1.5 or 3 Mb on the long arm of chromosome 22. This is one of the most common deletion syndromes affecting approximately 1:3000 live births. Affected individuals may be diagnosed shortly after birth due to the presence of a congenital heart defect. However, those individuals without a heart defect usually have a significant lag in time before diagnosis, despite multiple medical problems. Some of the associated conditions such as hypoparathyroidism or thymic aplasia require immediate therapy soon after birth. Other conditions such as the speech delay, school difficulties or the development of schizophrenia have their onset in childhood and adolescence, but would benefit from early recognition and treatment. Currently this microdeletion is detected through the use of fluorescent in situ hybridization demonstrating a hemizygous deletion on chromosome 22. While this assay is commercially available, it is expensive and time consuming to perform and requires a sample of whole blood. This makes the assay unsuitable for use in population screening. The specific aims of this proposal are to develop an assay using a DNA probe labeled with an infrared dye to detect a 2 fold copy difference in normal controls versus patients with the deletion using DNA extracted from dried blood spots. This assay could be used for diagnosis and as a population based screening test for this disorder. The sensitivity and specificity and reliability of the assay will be measured using a small cohort of known controls and affected patients (confirmed by FISH) with repeated measures, then assessed for reliability in a larger cohort of cases and controls and ultimately in an unknown population sample using newborn dried blood spots. The goal of this project is to develop an assay that is quick, sensitive, specific and can be run in a semiautomated fashion allowing for high throughput population screening. PUBLIC HEALTH RELEVANCE: Given the frequency of the 22q11 disorder, the relative complexity and the need for early intervention routine newborn screening for 22q11 Deletion syndrome is indicated. The high incidence of this disorder, along with the need for early intervention, makes 22q11.2 deletion syndrome a good candidate for newborn screening.

描述（由申请人提供）：Digeorge 综合征/腭心面综合征/22q11.2 缺失综合征是一种复杂的疾病，由于 22 号染色体长臂上有 1.5 或 3 Mb 的微缺失。这是最常见的缺失综合征之一，影响大约1:3000 活产。由于存在先天性心脏缺陷，受影响的个体可能在出生后不久被诊断出来。然而，尽管存在多种医疗问题，但那些没有心脏缺陷的人在诊断之前通常会出现明显的延迟。一些相关疾病，如甲状旁腺功能减退或胸腺发育不全，需要在出生后立即治疗。其他病症，例如言语迟缓、学习困难或精神分裂症的发展，都在儿童期和青春期发病，但早期识别和治疗将有益于这些病症。目前，这种微缺失是通过使用荧光原位杂交来检测的，证明了 22 号染色体上的半合子缺失。虽然这种测定方法可在商业上获得，但执行起来既昂贵又耗时，并且需要全血样本。这使得该测定不适合用于人群筛查。该提案的具体目标是开发一种检测方法，使用红外染料标记的 DNA 探针，使用从干血斑中提取的 DNA 来检测正常对照与缺失患者之间 2 倍的拷贝差异。该测定可用于诊断并作为针对这种疾病的基于人群的筛查测试。将使用一小群已知对照和受影响的患者（通过 FISH 确认）通过重复测量来测量测定的灵敏度、特异性和可靠性，然后在更大的病例和对照队列中以及最终在未知人群样本中评估可靠性使用新生儿干血斑。该项目的目标是开发一种快速、灵敏、特异且可以半自动方式运行的检测方法，从而实现高通量群体筛选。公共卫生相关性：考虑到 22q11 疾病的发生频率，22q11 缺失综合征的新生儿常规筛查相对复杂性和早期干预的必要性已被指出。这种疾病的高发病率以及早期干预的需要使得 22q11.2 缺失综合征成为新生儿筛查的良好候选者。