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

描述（由申请人提供）：Digeorge综合征/ velocofacial综合征/22q11.2缺失综合征是由于22号染色体长臂上有1.5或3mb的微缺失引起的一种复杂的疾病。这是影响约1:3000活产的最常见缺失综合征之一。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，那些没有心脏缺陷的人通常在诊断前有明显的时间滞后，尽管有多种医学问题。一些相关的情况，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、学习困难或精神分裂症的发展，在儿童和青少年时期就开始了，但如果及早发现和治疗，将会受益。目前，这种微缺失是通过荧光原位杂交检测到的，显示了22号染色体上的半合子缺失。虽然这种检测方法在商业上是可用的，但它昂贵且耗时，并且需要全血样本。这使得该试验不适合用于人群筛选。本提案的具体目的是开发一种使用红外染料标记的DNA探针的检测方法，以检测正常对照与从干血斑中提取DNA的缺失患者的2倍复制差异。该试验可用于诊断，并作为基于人群的筛查试验，这种疾病。该检测方法的敏感性、特异性和可靠性将通过一个由已知对照和受影响患者（经FISH确认）组成的小队列进行反复测量，然后在更大的病例和对照队列中进行可靠性评估，最终在使用新生儿干血点的未知人群样本中进行可靠性评估。该项目的目标是开发一种快速、敏感、特异的检测方法，并且可以以半自动方式运行，从而实现高通量人群筛查。公共卫生相关性：考虑到22q11疾病的频率，对22q11缺失综合征进行新生儿常规筛查的相对复杂性和早期干预的必要性。这种疾病的高发病率，以及早期干预的需要，使22q11.2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.