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

描述（由申请人提供）：Digeorge综合征/Velocardiofacial综合征/22q11.2缺失综合征是由于22号染色体长臂上1.5或3 Mb的微缺失引起的复杂疾病。这是最常见的缺失综合征之一，影响约1：3000的活产。受影响的人可能会被诊断出生后不久，由于存在先天性心脏缺陷。然而，那些没有心脏缺陷的人通常在诊断前有一个显着的时间滞后，尽管有多种医疗问题。一些相关的疾病，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。其他情况，如语言迟缓、上学困难或精神分裂症的发展，都是在儿童和青少年时期发病的，但如果及早识别和治疗，会有好处。目前，这种微缺失是通过使用荧光原位杂交检测，证明22号染色体上的半合子缺失。虽然这种测定是商业上可获得的，但它昂贵且耗时，并且需要全血样品。这使得该测定不适合用于群体筛查。本提案的具体目的是开发一种使用红外染料标记的DNA探针的测定法，以使用从干血点提取的DNA检测正常对照与缺失患者的2倍拷贝差异。该测定可用于诊断和作为该疾病的基于群体的筛选试验。将使用已知对照和受影响患者（经FISH确认）的小队列重复测量，然后在较大的病例和对照队列中评估可靠性，并最终使用新生儿干血斑在未知人群样本中评估可靠性。该项目的目标是开发一种快速、灵敏、特异的检测方法，并以半自动方式运行，以实现高通量人群筛查。公共卫生相关性：鉴于22 q11疾病的频率，22 q11缺失综合征的相对复杂性和早期干预的必要性，常规新生儿筛查。这种疾病的高发病率，沿着需要早期干预，使得22 q11.2缺失综合征成为新生儿筛查的良好候选者。

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.